Homer’s Iliad reports detailed descriptions of war traumas, with precise anatomical references, so that the Iliad can be considered the first trauma registry. We aimed to analyse the Iliad from the perspective of a modern trauma registry: that is, to find historical and local prognostic factors through the epidemiological study of the reported traumas.Two different editions of Homer’s Iliad—one in English and one in Italian—were thoroughly studied and epidemiological data were statistically analysed.148 reports of human traumas were analysed. The majority of traumas (73.6%) involved Trojan warriors, with spears being the most frequent wounding agent (71%). Overall mortality was 84.5% and was higher in the Trojan field (90.8% vs 61.5%). Despite the high mortality, median New Injury Severity Score (NISS) was low, probably due to high prevalence of penetrating mono-systemic trauma. Median NISS was higher in the Trojan group. Compared to the Achaeans, the Trojans had more torso injuries, whereas Achaeans had more injuries to limbs and superficial tissues. However, in both fields, head and neck were more frequently injured.Homer’s Iliad gives us an interesting insight into war traumas during the siege of Troy. The reported higher mortality within the Trojan army can be explained not only by poetic reasons but also by different military skills. The Iliad is a Greek epic poem, traditionally attributed to Homer. According to Herodotus, it might have been written in the ninth century BC and describes the Trojan War, probably fought around the twelveth century BC, during the Bronze Age. The war was actually a 10-year siege of Troy (or Ilium) by allied Greek armies. According to Greek mythology, the origins of the Trojan War lie in a banquet held on Mount Olympus for the wedding of Peleus and Thetis, when Eris (the goddess of discord), not invited, tossed a golden apple with ‘to the most beautiful’ inscribed on it. This generated a quarrel between the goddesses Hera, Athena and Aphrodite about which of them was the fairest. To resolve the dispute, Zeus elected the young Trojan shepherd Paris to act as a judge. Each of the three competitors tried to convince Paris with a reward. Hera offered the kingdom of Europe and Asia, Athena offered wisdom and skills and Aphrodite offered Helen of Sparta, the most beautiful of all worldly women, who was married with Sparta’s king Menelaus, brother of Mycenae’s king Agamemnon. Paris awarded the golden apple to Aphrodite and obtained his reward. Menelaus sought help from his brother Agamemnon and other Achaean kings to rescue Helen and they gathered a large army, which besieged Troy for 10 years. The battles were mainly fought outside the walls of Troy.The historical existence of Troy was put in doubt for many centuries, but the German archaeologist Heinrich Schliemann in 1868 found the remnants of what is now considered the mythological Troy, in present-day Turkey. The excavations found several different layers of buildings and one of them shows signs consistent with the alleged fire started by the Achaeans when they conquered and destroyed Troy. The most accredited version of facts is that the Trojan War was the outcome of a longstanding fight between Achaeans and Trojans for the control of the naval routes to the Black Sea, with Troy being built in an advantageous position on the Turkish shores of Hellespont.There is no real evidence that the Trojan War was a real one-stage conflict, but at the same time, there is no counter evidence. Some authors state that Homer just collected tales of sporadic and recurrent sieges and attacks of Troy by Achaeans in the Bronze Age and other propose that the Trojan War was a specific conflict. Despite not being professional historians or archaeologists ourselves, we tend to favour this second hypothesis mostly on the basis that different aspects of the Trojan War have been narrated also by other ancient Greek authors. In the Iliad, battles and duels are narrated in abundant detail. In particular, wounds and injuries are described quite thoroughly, so that some authors wondered if Homer himself had a medical background . Mostly,The recent epidemiological approach to war or civilian traumatic injuries occurs through the implementation of trauma registries. These are useful tools to monitor the epidemiology, pathways, protocols and outcomes of trauma to identify modifiable risk factors for primary and secondary trauma morbidity and mortality. Trauma registries require data to be standardised, periodically analysed and benchmarked on an international basis .In this work, we analyse the Trojan War injuries from a trauma registry perspective to study the epidemiology of war trauma during that conflict and, where possible, to identify the factors leading to the ultimate outcome of the war.t test) or non-parametric tests (Mann–Whitney U test). All the considered variables were taken into account into a binomial logistic regression analysis so as to identify independent ‘prognostic’ factors.Homer’s Iliad in the English translation by Martin Hammond  and in t2 = 15.34; p = 0.009). Blunt, penetrating and multisystem injuries were equally distributed between the two groups.We identified 148 human traumas described in the Iliad (Table p < 0.001). The stratification of NISS into mild, moderate and severe showed a higher prevalence of moderate and severe NISS in the Trojan army with respect to Achaeans (p < 0.001).The vast majority of injuries were fatal and overall mortality for trauma was 84.5% 125/148). Death was immediate, on the scene, in most cases. Mortality was much higher among Trojans than in the Achaean group (90.8 vs 61.5%). NISS could be calculated for 145 cases, while in three cases, there was no information on the mechanism of injury. NISS values were skewed to the right (the right tail is longer than the left one—skewness 1.26) . As expected, most traumas were penetrating (87.8%) and were associated with higher mortality as compared to blunt trauma .Injuries to head and neck were the most frequent trauma in the overall series (27.0%), but Achaeans were more frequently hit in the limbs (35.9%) as compared to head and neck (25.6%). Compared to the Achaeans, the Trojans had more chest and abdominal injuries . The distribution of wounds was significantly different between the two fields , weapon, mechanism of injury, NISS rank and body system involved were all significantly associated with the risk of death Table .Table 2UBinomial logistic regression analysis for mortality  showed that only the variable “field” was independently related to the death outcome Table . BelongiThe Trojan War as described by Homer was a peculiar kind of fight. Allegedly, the Achaean allied armies attacked the fortified city of Troy, but the actual fight was not a proper siege business. In fact, the vast majority of fights and duels happened on open fields outside the walls of Troy and the Trojan army was not fully employed to defend the town walls. Moreover, until the use of the Trojan horse, no significant attack was launched against the town itself, probably due to the lack of effective siege engines.The type of war reported in the Iliad is the so-called “champion warfare” or “single combat” or “monomachy”, where the outcome of the battle depended on single duels between selected “champions” on both sides, probably aimed to avoid unnecessary bloodshed in the total lack of military discipline . MonomacThe Iliad has long been studied to gain an insight into battle injuries, anatomical knowledge and trauma management in Ancient Greece , 3, 9. IThe number of casualties reported in the Iliad (148) is surprisingly low with respect to the length of the war (10 years); however, it should be noted that the Iliad’s action only covers a period of 52 days in the final year of the conflict. It is possible that Homer selected only those involving the most significant heroes on either side, but the detailed description of duel and traumatic injuries may suggest that Homer had observed similar events directly.Most casualties involved Trojan warriors, probably due to the evident dominance of the Achaean armies prevailing in number, importance and strength; but other factors, including political considerations, might have played a role.While the overall median NISS is low (25), mortality is very high at 83.1%. This is likely due to the penetrating nature of most injuries, as well as the poor physical protection and limited availability of effective treatment. It should be noted that most mortalities occurred immediately after the injury. The unrealistic frequency of sudden death in the Iliad has previously been noted; this might be regarded as a poetic convention so as to increase the dramatic effect and maintain the rhythm of the narration [As mentioned, mortality was much higher among Trojans than within the Achaean group (90.8% vs 61.5%) and median NISS is higher for Trojans (25 vs 16). Injury distribution varies significantly between the two opposing armies. While in both groups the most common injury type is head and neck trauma, Trojans experienced a higher incidence of chest and abdomen wounds as compared to Achaeans who, on the other hand, suffered a higher incidence of limb injuries. This can be due to different armours and armaments between Achaeans and Trojans. Unfortunately, Homer’s description of armours is not always reliable as an element of fiction seems to be always present. In fact, appearance and strength of heroes in the Iliad are usually symbolically functional to their importance and relevance .Shields were usually long so as to cover the whole body, but small round shields were also used along with greaves to protect the legs. Protective armours including helmets were usually made of bronze, variably mixed with other materials, such as bull’s hide. For instance, Ajax’s shield had several layers of bull’s skin and one layer of bronze. On the other hand, Paris did not wear any armour but only a leopard-skin, probably to signify that he was protected by a powerful goddess.Many warriors on both sides used a waist-long cuirass made of several bronze plates covering the whole torso but leaving the neck exposed . This caNo significant difference between Achaeans and Trojans is described with regard to weapons and armours; this factor, therefore, may not be crucial in determining the difference in mortality. However, NISS is significantly higher for Trojans than for Achaeans, thus highlighting a possible difference in military skills and strategy, if not an unbalanced divine protection.This leaves the question open: why was the mortality rate significantly higher among Trojans than among Achaeans? One possibility is that in his poem Homer is psychologically ‘siding’ with Achaeans, and rather inclined to describe combats where Achaean heroes survive their wounds, while Trojans more frequently succumb.We raise the hypothesis that the different mortality rate might be due to many Achaeans being wounded by arrows, whereas Trojans more often succumbed to spears. Homer may be expressing here some sort of moral criticism of Trojan warfare, relying on distant attacks rather than close combat, in contrast to the ‘heroic’ attitude displayed by Achaeans. In fact, Achaeans incurred a fourfold risk of being hit by an arrow than Trojans. To the contrary, almost three quarters of Trojan wounds were due to spear. This difference should not surprise if we consider the usual dynamics of sieges, where defenders tend to avoid body-to-body fight as much as possible and try to repel the attackers from behind the walls of the fortified town.The skewed distribution of NISS scores towards the left side of the spectrum shows that the vast majority of traumas involved only one system, which is typical of penetrating injuries. Only a few cases had multisystem trauma, and this does not differ between the two fields. The description of multiple traumas may be functional to creating a more dramatic effect but also to demonstrating the anger of the attacker due to personal, more than collective, reasons. The outcome of the duel between Achilles and Hector is paradigmatic.In contrast to modern war traumas, where explosions account for most lethal casualties , penetraClearly, the site of injury may also be associated with outcome, mortality being highest in combatants with abdominal or chest injuries. In fact, Achaean and Trojan warriors were usually well shielded by a protective armour covering their torso but leaving neck and limbs exposed; for this reason, a penetrating injury to the torso would have been associated with much more kinetic energy compared to injuries of exposed regions. Therefore, abdominal and chest injury were less likely, but often lethal.In conclusion, the Iliad gives us an interesting insight into war traumas in ancient Greece. The reported higher mortality among Trojans can be explained by poetic and political reasons, but also by different military techniques and skills. Although the Iliad evidences military superiority of the Achaean army over the Trojans, it is for the historian to understand why the final victory of the Achaeans could be obtained only through Odysseus’ stratagem of the Trojan horse.


Mage = 42.05 years, SD = 16.49 years) were randomly assigned into either an experimental condition to experience a disaster or a control condition. Participants in the experimental condition reported a lower level of materialism than the scores of their counterparts in the control condition. Such effects were mediated by both mortality salience and gratitude. Participants in the experimental condition reported higher levels of both mortality salience and gratitude simultaneously. Mortality salience strengthened materialism, but gratitude weakened materialism. These findings highlighted the duel-existing mechanisms underlying the relationship between disaster experience and materialism.Studies have yielded inconclusive findings regarding the relationship between disaster experience and materialism. Whereas some have found a positive relationship, others have reported a negative relationship. To clarify the mechanisms underlying these mixed findings, we proposed and examined two mechanisms, namely mortality salience and gratitude. A total of 214 participants ( The International Federation of Red Cross and Red Crescent Societies 2017) defines a disaster as a sudden, calamitous event with three main features: (1) it interrupts the normal functioning of a community or a society; (2) it causes human, material, and economic or environmental losses; and 3) its impacts exceed the community’s or society’s coping capacity by using its own resources. According to this definition, coronavirus disease (COVID-19) can be categorized as a disaster [7 defines its impaDisasters influence affective experiences ,7, decisAnother line of research has suggested that disasters are associated with a lower level of emphasis on money, such as preferences on donations and prosocial behavior . According to Schwartz , the behPrevious work has primarily focused on one mechanism that might be induced by experiencing a disaster, leading to inconsistent findings regarding the relationship between disaster experiences and materialism. Given that a disaster experience may elicit complex thoughts, it is likely that either mechanisms favoring or not favoring materialism can be induced via the disaster experiences. The aim of the current study was to clarify this issue. In particular, we argue that disasters elicit a diverse set of cognitive and affective components. For instance, experiencing a disaster that can cause death may elicit the awareness of the unpredictability of one’s death . People who have survived a disaster may also feel grateful. Such a feeling of gratitude may be caused by the thoughts that they did not die as some of their counterparts did. It may also be caused by the possibility that they received help and support from others when experiencing the disaster. Although a large number of studies have examined the relationship between experiencing a disaster and mortality salience, and that between experiencing a disaster and gratitude, few studies have considered the relationship between disasters and materialism from a perspective that considers both constructs. Therefore, we aimed to clarify the relationship between disasters and materialism by focusing on two psychological responses to a disaster, namely mortality salience and the feeling of gratitude.Disasters foster not only physical threats, but also psychological threats, such as the fear of death . MortaliIn addition to inducing mortality salience, disasters can induce feelings of gratitude ,36. GratDuring a disaster, individuals may feel gratitude for two reasons. First, individuals may receive unanticipated help during a disaster. For instance, governments, communities, and others provide support for affected individuals by constructing and launching economic and health support structures , as wellTerror management theory  posits tThe positive relationship between mortality salience and materialism has been supported by a number of empirical studies. Kasser and Sheldon  found thGratitude is a common positive emotion to help people find relief , which cPolak and McCullough  argued tAs of 31 December 2020, COVID-19 has affected 219 countries and territories, with more than 85 million cases of infected people, and more than 1.8 million deaths . As COVIH1), and that mortality salience would be positively associated with materialism (H2), whereas gratitude would be negatively associated with materialism (H3).We argue that the inconsistent relationship found between disasters and materialism is attributable to the fact that disaster experience may induce dual psychological systems, namely mortality salience and gratitude. When individuals focus on mortality salience, they would show a higher level of materialism as a way of coping with anxiety. When individuals focus on gratitude, they would show a lower level of materialism because the feeling of gratitude has eased anxiety caused by the disaster. We adopted an experimental design to study the causal relationship between disasters and materialism. In particular, we examined the mediating roles of mortality salience and gratitude in this relationship. We manipulated the disaster experience by asking participants to watch a video of street view in Wuhan, China during the COVID-19 lockdown in 2020. In the non-disaster focus control condition, participants viewed a street view in Hangzhou, China taken in 2018. We hypothesized that participants in the experimental condition would report higher levels of both mortality salience and gratitude than the control condition  from 22 provinces in China participated in the study in May 2020. This study was approved by the Institutional Review Board of the Education University of Hong Kong. All of the participants completed an informed consent form. The invalid responses of 21 participants were excluded from data analysis because of the technical problems with the online experiment . The final sample comprised 193 participants .A convenient sampling method was adopted in this study. Participants were recruited through university mass mail systems and the public WeChat platform . Based on power analysis conducted by llection , after sn = 86) or the control condition (n = 107). In each condition, participants were asked to watch a video clip with careful attention. They were informed that they would be asked some questions related to the content of the video in the next part of the experiment. After watching the video, the participants were required to recall “a vivid personal experience that was directly or indirectly relevant to the watched video, which could be positive/negative/neutral,” and to provide basic information on the experience in five areas: “When did it happen?”, “Where did it take place?”, “Who was involved?”, “What happened?” and “How did you feel/think?”. They were asked to rate to what extent they could memorize the experiences. Next, the participants were instructed to respond to questions regarding their actual affect and attitudes toward materialism, as well as demographic information. Following these steps, each of the participants received a supermarket coupon worth approximately USD 7.Participants were randomly assigned to either the experimental condition , showing the daily life of healthy people, reunion dinners with friends and family, and a crowded and thriving tourist resort. Similar to Wuhan, Hangzhou is a well-known city and one of the financial centers in China.Yes”, 0 = “No”. In the experimental condition, 77.91% of the experiences were coded as relevant to COVID-19, whereas only 0.93% of the experiences written by participants in the control condition were coded as relevant to COVID-19, X2  = 123.79, p < 0.001. The results indicated that the manipulation was successful.As a manipulation check to ensure that the video presented in the experimental condition successfully activated participants with thoughts related to COVID-19, two independent raters read the written description provided by the participants in the two conditions and coded whether the described experiences were relevant to COVID-19 on a binary scale, with 1 = “completely disagree” to 5 “completely agree”. More materialistic individuals tend to place material property at the core of their lives and use their possessions to measure their success and happiness, and consider possessions as an indicator of a central position. As the measure consists of nine items, we used Cronbach’s alpha to assess the scale’s reliability for our participants. In the present study, the internal consistency was acceptable (α = 0.73).We measured materialism using the short form of the Material Values Scale (MVS) as updated by Richins . The scano” or 1 “yes” to answer whether they had thought about death. They indicated the extent of the thought on a 7-point Likert scale from 1 “very weak” to 7 “very strong”. We multiplied the responses of these two questions so that the scores of those who did not think about death when watching the video were coded as 0.Participants answered two questions regarding whether and to what extent they had been thinking about death when they watched the video or wrote about their experiences. They used 0 “not at all” to 5 “very much”.Participants were asked to indicate the intensity of feelings of gratitude when watching the video or writing their experiences on a 5-point Likert scale ranging from 1 “not at all” to 5 “very much”.After recalling relevant personal events, participants were asked to indicate the level of accuracy of their memory on a 5-point scale from 1 “We controlled for participants’ personal income and socioeconomic status  because M = 1.57, SD = 2.31) and on gratitude  than the scores of participants in the control condition on mortality salience ), and on gratitude ). There was also a significant difference in materialism in the two conditions. Compared with those in the control condition , participants in the experimental condition expressed a significantly lower level of materialism ) ) see . CorrelaWe first conducted separate analyses to test the mediating role of mortality salience and gratitude. We conducted simple mediation analyses using the PROCESS macro version 3.4.1 (Model 4)  with theb = 1.24, SE = 0.26, p < 0.001, 95% CI = ). A higher level of mortality salience was related to more materialism ). However, the disaster manipulation showed significant negative effect on materialism, −0.17. After taking the effect of mortality salience into account, the effect of disaster manipulation on materialism was great ). Importantly, the indirect effect of disaster manipulation on materialism via mortality salience was significant, the indirect effect estimate = 0.07, 95% CI =   , showingb = 0.44, SE = 0.17, p = 0.009, 95% CI = ). A higher level of gratitude was associated with a lower level of materialism ). The disaster manipulation showed significant effect on materialism, −0.17. After taking the effect of gratitude into account, the effect of disaster manipulation on materialism was weakened ). Importantly, the indirect effect of disaster manipulation on materialism via mortality salience was significant, the indirect effect estimate = −0.05, 95% CI = , showing that gratitude was a significant mediator on reducing materialism.As shown in b = 1.26, SE = 0.26, p < 0.001, 95% CI = ) and more gratitude ) simultaneously compared to the control condition. More mortality salience was related to more materialism ), whereas more gratitude was related with less materialism ). The disaster manipulation showed a significant effect on materialism, −0.17. After taking into account the disaster manipulation’s indirect effect through mortality salience and gratitude, the effect of disaster manipulation on materialism was significant ). Moreover, the indirect effect through mortality salience showed a significant positive effect (0.06) with 95% CI =  on materialism, whereas the indirect effect through gratitude showed a significant negative effect (−0.04) with 95% CI =  on materialism (With considering the mediating roles of both morality salience and gratitude, we received results to support both underlying mechanisms. In the parallel mediation model, being in the experimental condition was associated with a higher level of mortality salience (erialism .By activating disaster-related thoughts through video clips in an online experiment, the current study investigated the effect of disasters on materialism and the mediating roles of mortality salience and gratitude underlying the influence. We found that when participants were reminded of disasters, they reported greater mortality salience and gratitude than did participants in the control condition. Importantly, both mortality salience and gratitude significantly mediated the influence of disasters on materialism with the former one strengthening materialism but the latter one weakening materialism.Materialism has emerged as an increasingly important research topic and attracts scholars in various fields, including political science , social Most previous studies on disaster have focused on the role of mortality salience. Fewer studies have highlighted the role of gratitude. Our study demonstrates the benefits of feeling gratitude after a disaster. In particular, feelings of gratitude induced by a disaster experience may lead individuals to consider more positive ways to cope with the effects of disaster ,36 and rThe competing effects of mortality salience and gratitude have implications for theoretical and empirical exploration of needs satisfaction in the context of disasters. Maslow  proposedOur findings offer a new perspective on the mechanism of individuals’ emotional responses to disasters and their impacts on personal values during the COVID-19 pandemic. First, our findings suggest that a disaster experience could trigger a range of emotional responses simultaneously. The effects of disasters may depend on which emotions have been triggered. Adaptive emotions, such as gratitude, may help individuals to better cope with a disaster. Other emotions, such as anxiety caused by mortality salience, may worsen individuals’ experiences. Future studies could pay more attention to the network of emotions induced by disasters. Second, the study examined the mediating role of gratitude in the relationship between disasters and materialism. Other studies have also demonstrated the benefits of feeling gratitude during the COVID-19 pandemic. For instance, Jiang  found thWe acknowledge some limitations of the current study. First, we relied on self-reported materialism. Future studies should adopt behavioral indexes of materialism, such as donations, to validate our findings. Second, we adopted an experimental design in which disaster experience was manipulated, which was only able to capture the immediate temporary effect of disaster experiences on materialism. A longitudinal study may better clarify the long-term relationships between disaster experience, materialism, mortality salience, and feelings of gratitude. Third, the priming materials of the current study focused on COVID-19; we did not examine whether the proposed model could be applied in other disaster contexts. Although the relationships among disaster, mortality salience, gratitude, and materialism were validated in multiple disaster settings, the proposed model has not been examined in another disaster context. Future studies should further validate the findings in other disaster-specific contexts. Fourth, because we relied on the study conducted in China, the generalization of findings could only be limited under the Chinese context. Because of the potential impacts of sociocultural factors on materialism , the finTo conclude, we examined the effect of disasters on materialism and how this relationship is mediated by mortality salience and gratitude. We found that a disaster experience decreased materialism. In particular, disaster experience triggered higher levels of both mortality salience and gratitude simultaneously. Mortality salience was associated with a higher level of materialism, whereas gratitude was associated with a lower level of materialism. By clarifying these two mechanisms, our findings provide insight into the relationship between disasters and materialism.


Dear Sir,We read with interest the Letter to the Editor “It is time for the nuclear medicine community to define a unit for the total lesion glycolysis (TLG) and similar metrics” by Duarte and Sapienza . We have18F-fluorodeoxyglucose (FDG)-PET has had a dominating presence for decades. Hence, references to metabolism and glucose consumption have claimed and narrowed down the concepts behind MTV and TLG [molecular tumour volume would appropriately define the tumour volume defined by a non-metabolic ligand. An added benefit is that it leaves the familiar MTV acronym intact. Conversely, TLG needs a rebranding. To define the product of SUVmean and MTV, we suggest total lesion activity (TLA), which is a more neutral term, as activity does not refer to the specific type of target involved. and TLG . In fact and TLG , 5. Regamean and MTV) could all be expressed in a unit of volume. In fact, TLG and TLA can be seen as a normalized tumour volume . Although a trivial issue, if we had to choose one such unit, we would favour mL over cm3 or cc, since Bq/mL is the common activity concentration unit in PET DICOM headers. As a side note, online search returns significantly more results when searching “metabolic tumor volume” or “total lesion glycolysis” with “mL”, rather than with “cm3” or “cc”, suggesting a general preference for the former.As for the units of each metric, that of SUV needs to be sorted out first. There is an ongoing disagreement in the community as to whether SUV has for unit g/mL or is unitless under the assumption that the average body density is close to 1 g/mL, i.e. the density of water. Even the two authors of this letter are divided on this question, one preferring the former (AR) and the other the latter scheme (JMB)! To solve this issue, we propose to explicitly insert the constant reflecting the assumption (i.e. 1 g/mL) in the denominator of the SUV formula, thus cancelling the units of SUV. Accordingly, not only MTV, but also TLG and TLA . TLF is the total integrated activity, say in Bq, in the lesion  divided by decay-corrected administered activity (in same units as above). In current viewing software, this can easily be obtained by dividing TLG or TLA by the estimated body volume in mL (based on either body weight or lean body weight as used to compute SUV and TLG or TLA). TLF is a unitless metric with a predefined and intuitive scale, that is, from 0 to 100%. By contrast, the TLG or TLA scale is different for each patient, as it theoretically spans up to the estimated patient volume.More importantly, we wish to propose a practical, alternate metric for molecular tumour burden: We propose to routinely report TLF in addition to other metrics such as MTV and TLA. A feature of TLF is that it is independent of body habitus indices. TLF may in fact better illustrate the relative importance of the tumour burden for patients of different sizes and thus facilitate interpatient comparisons. For example, two patients having an identical TLA of 10,000 mL would be deemed to have the same tumour burden by this metric. However, if these patients weigh 50 kg and 100 kg, they will have TLFs of 20% and 10%, respectively. In such a scenario, TLF may better convey that the former patient has a larger relative tumour burden and may thus have potentially poorer outcome given relatively smaller reserve by the body to encounter the tumour load, which can be investigated in different outcome prediction studies. In other words, it is plausible that TLF may improve prediction of outcome relative to TLA (and other metrics such as SUV), and by more routinely reporting this metric, such a hypothesis can be further evaluated for different diseases and radiopharmaceuticals. Furthermore, when used to assess whole-body tumour burden, TLF becomes a straightforward measure of the tumour sink effect, that is, the fraction of administered activity sequestered in the tumour that is not available for uptake by healthy tissues . This ha177Lu-DOTATATE post-treatment quantitative SPECT accurately predicted the late MTV-based response assessed with 68Ga-DOTATATE PET [Metabolic response using FDG-PET is commonly based on change in maximum or peak SUV, as in PERCIST . HoweverTATE PET .metabolic with molecular within MTV and renaming TLG to TLA . Furthermore, we propose TLF as a simple, unitless and intuitive way to further quantify overall tumour avidity especially in the era of theranostics.In conclusion, to widen the scope of MTV and TLG beyond FDG-PET, we propose replacing Jean-Mathieu Beauregard.Arman Rahmim.


Poly ADP-ribose polymerase inhibitors (PARPi) have transformed ovarian cancer (OC) treatment, primarily for tumours deficient in homologous recombination repair. Combining VEGF-signalling inhibitors with PARPi has enhanced clinical benefit in OC. To study drivers of efficacy when combining PARP inhibition and VEGF-signalling, a cohort of patient-derived ovarian cancer xenografts (OC-PDXs), representative of the molecular characteristics and drug sensitivity of patient tumours, were treated with the PARPi olaparib and the VEGFR inhibitor cediranib at clinically relevant doses. The combination showed broad anti-tumour activity, reducing growth of all OC-PDXs, regardless of the homologous recombination repair (HRR) mutational status, with greater additive combination benefit in tumours poorly sensitive to platinum and olaparib. In orthotopic models, the combined treatment reduced tumour dissemination in the peritoneal cavity and prolonged survival. Enhanced combination benefit was independent of tumour cell expression of receptor tyrosine kinases targeted by cediranib, and not associated with change in expression of genes associated with DNA repair machinery. However, the combination of cediranib with olaparib was effective in reducing tumour vasculature in all the OC-PDXs. Collectively our data suggest that olaparib and cediranib act through complementary mechanisms affecting tumour cells and tumour microenvironment, respectively. This detailed analysis of the combined effect of VEGF-signalling and PARP inhibitors in OC-PDXs suggest that despite broad activity, there is no dominant common mechanistic inter-dependency driving therapeutic benefit.The online version contains supplementary material available at 10.1186/s13045-021-01196-x. To the Editor,BRCA and other homologous recombination repair (HRR) pathway components which sensitize tumors to PARPi [BRCA wild-type tumours [Olaparib is a first-in-class poly ADP-ribose polymerase inhibitor (PARPi) for treatment of recurrent platinum-responding ovarian cancer (OC)  with delto PARPi . To incrto PARPi , 3. Thisto PARPi . Combinito PARPi , provide tumours . Our preP < 0.0001; odds ratio of 3.9) across the OC-PDX panel, with greater antitumor benefit in tumours refractory to platinum and olaparib. Tumour control seen at 4 weeks  inhibition, thus inducing a contextual tumour BRCAness [RAD51 expression across a panel of OC cell lines (Additional file BRCA or RAD51 in vitro was only achieved at ≥ 3 μM concentrations of cediranib (Additional file BRCA or RAD51 modulation was not prevented by silencing of E2F4 (Additional file PDGFRB expression (Fig. Extensive analysis was performed to identify potential drivers of combination efficacy. Consistent with its mode of action , cediranBRCAness . Our anaThe benefit of the combination in controlling tumour progression was confirmed in three disease relevant orthotopic OC-PDXs Fig.  that mimIn summary, we show that the addition of cediranib enhances the antitumor efficacy of olaparib in both olaparib-sensitive and olaparib-resistant OCs. Pre-clinical activity was not associated with a mechanism priming response to cediranib or olaparib. Rather the agents appear to be complementary, with olaparib impacting DNA repair and cediranib modulating tumour vasculature, to increase response across the entire OC-PDXs panel. Our extensive experimental in vivo efficacy data reproduce clinical observations, while our comprehensive mechanistic analysis suggests the combination effect is largely driven by targeting independent mechanisms, rather than inducing specific changes that prime response to a partner drug.Additional file 1.Supplementary Figure S1. Characteristics of the OC-PDXs used for drug efficacy testing. Supplementary Figure S2. Haploinsufficiency of the BRCA2 mutation in MNHOC182 and MNHOC18. Supplementary Figure S3. Transcriptional status of key genes in OC-PDXs and BRCA1 promoter methylation. Supplementary Figure S4. Antitumor activity of the olaparib and cediranib combination therapy at 8 weeks of treatment. Supplementary Figure S5. Cediranib reduced MNOC124 tumour associated vasculature but did not affect the expression of HRR genes. Supplementary Figure S6. Rapid and prolonged tumour response by the combination olaparib and cediranib in platinum-sensitive and olaparib-sensitive OC-PDXs. Supplementary Figure S7. Reduction of tumour associated vasculature by cediranib in the OC-PDXs cohort used for drug efficacy testing. Supplementary Figure S8. Hypoxia does not trigger the downregulation of HRR in ovarian cancer cell lines. Supplementary Figure S9. RAD51 downregulation is not related to PDGFRB pathway. Supplementary Figure S10. The combination olaparib and cediranib demonstrated greater efficacy than either monotherapy in OV2022 tumours: no therapy-induced changes in HRR genes could be detected. Supplementary Figure S11. No common changes in gene expression by cediranib treatment were identified in OC-PDXs that benefit from the combination therapy. Supplementary Figure S12. Survival advantage is lost upon treatment interruption. Supplementary Table S1. List of genes analysed by Fluidigm high-throughput gene expression analysis.Additional file 2. Methods.


Among the 49 metabolites identified, 24 were significantly affected throughout tumour evolution and 21 were significantly affected regarding animal age. The altered metabolites were mainly related to increased amino acid levels and changed energetic metabolism in the skeletal muscle, suggesting an expressive catabolic process and diverted energy production, especially in advanced tumour stages in both groups. Moreover, these changes were more severe in weanling hosts throughout tumour evolution, suggesting the distinct impact of cancer cachexia regarding the host’s age, highlighting the need to adopting the right animal age when studying cancer cachexia.Cancer cachexia is a severe wasting condition that needs further study to find ways to minimise the effects of damage and poor prognosis. Skeletal muscle is the most impacted tissue in cancer cachexia; thus, elucidation of its metabolic alterations could provide a direct clue for biomarker research and be applied to detect this syndrome earlier. In addition, concerning the significant changes in the host metabolism across life, this study aimed to compare the metabolic muscle changes in cachectic tumour-bearing hosts at different ages. We performed  Cancer cachexia is a multi-factorial syndrome associated with skeletal muscle wasting with or without adipose tissue loss, chronic systemic inflammation, anorexia, poor prognosis, and reduced survival . DependiCachexia is also considered to be a multi-organ syndrome, since it leads to multiple organ metabolism changes such as in the heart, liver, brain, white and brown adipose tissue, and especially skeletal muscle tissue, the most affected one . Fearon As cachexia progresses, proteolysis of myofibrillar proteins increases . This caAmong the morphometric parameters , we obseIn the young adult tumour-bearing animals, the AWa group had a significantly higher tumour relative weight when compared with initial tumour-bearing animals (AWi), and tumour weight was similar to that in intermediate tumour-bearing animals (AWm). In the weanling group, the relative tumour size was higher in the advanced tumour animals (WWa) than the initial tumour (WWi) and intermediate tumour (WWm) animals. However, there was no difference in the relative tumour size between WW and AW animals b.Regarding the relative gastrocnemius muscle weight, all tumour-bearing animals in the weanling group presented a significant reduction when compared with WC animals. In the young adult groups, only AWa animals had a reduction in the gastrocnemius weight when compared with the AC group. Considering the body development in weanling animals, we observed a significantly higher relative gastrocnemius weight in the WC, WWm, and WWa groups compared with the respective young adult groups c.Concerning the nitrogen balance, we observed a significant reduction in the intermediate and advanced tumour-bearing groups, independent of age, compared with non-tumour-bearing rats. The initial tumour stage was significantly different only in young adult groups compared with the AC group. Weanling animals differed from young adults in the initial tumour stage only d.Among the 49 gastrocnemius muscle metabolites identified , 24 wereIn the amino acids and derivatives category, in the weanling groups, seven metabolites were significantly increased due to tumour effects  and three metabolites were significantly decreased . Meanwhile, in the young adult groups, only eight metabolites were significantly increased  .In the weanling group, regarding the energetic metabolism/TCA cycle, two metabolites significantly increased with tumour evolution  and two metabolites were significantly decreased . In the nucleotide synthesis and biosynthesis of secondary metabolites and cofactors categories, four metabolites were significantly increased  and in the lipid metabolism category, choline was increased (WWa > WWi and/or WWm). In young adult groups, four metabolites were significantly enhanced by the tumours’ effects  in these three categories .Analysis of these changed metabolites showed that the most impacted pathways in WW groups affected by tumour evolution were aminoacyl-tRNA biosynthesis; valine, leucine, and isoleucine biosynthesis; phenylalanine, tyrosine, and tryptophan biosynthesis; nitrogen metabolism; and D-glutamine and D-glutamate metabolism. In the AW groups during tumour evolution, the most impacted pathways were aminoacyl-tRNA biosynthesis; valine, leucine, and isoleucine biosynthesis; phenylalanine, tyrosine, and tryptophan biosynthesis; and vitamin B6 metabolism .In the amino acids and derivatives category, eight metabolites were significantly increased in weanlings and decreased in the young adult group , and three metabolites were significantly decreased in weanlings and increased in the young adult group  .Regarding the energetic metabolism, five metabolites were significantly increased in weanlings and decreased in the young adult group  WWm > AWm; NADP+ (nicotinamide adenine dinucleotide phosphate): WC > AC and WWi > AWi and WWm > AWm; and xanthine: WC > AC and WWa > AWa). In the nucleotide synthesis and biosynthesis of secondary metabolites and cofactors category, two metabolites were significantly increased in weanlings and decreased in the young adult group  and only three metabolites were significantly decreased in weanlings and increased in the young adult group  .Analysing these altered metabolites, we observed that the pathways most impacted by the tumour effects in the WW group vs. the AW group were aminoacyl-tRNA biosynthesis, nitrogen metabolism, D-glutamine and D-glutamate metabolism, histidine metabolism, β-alanine metabolism, and glyoxylate and dicarboxylate metabolism .In cancer cachexia, the mechanisms related to this severe wasting condition are still not fully understood ,14. SeveIntense body weight loss is expected during cancer cachexia, as verified in the AW animals in this study, and similar to others’ results for this same tumour model ,28,29. TThese alterations were accompanied by metabolic changes in the amino acids and derivates category in gastrocnemius tissue of both the WW and AW groups. Seven (the branched chain amino acids (BCAAs) isoleucine, leucine, and valine, and creatine, phenylalanine tryptophan, and tyrosine) and eight  metabolite levels were augmented in WW and AW animals, respectively, where some of these alterations followed other studies ,36. TsenStill regarding the amino acid category, we also found augmented phenylalanine in the WWa and AWa groups and an increase in tryptophan concentration only in the WWa group, likely indicating intense spoliation in these animals. Similarly, Lautaoja and collaborators  found phGlutamate and glutamine decreased in WW animals with tumour growth but remained the same in the AW animals. These amino acids are related to TCA as an intermediate precursor to ATP production or as a carbon precursor to the synthesis of nucleotides, and the interorgan metabolism of nitrogen and carbon metabolism . In addiAnother point to discuss regarding the metabolomics results is the reduction of carnosine in WWi rats, which may be associated with possible targeting of this metabolite by the tumour. Recent research pointed out the potential physiological effects of carnosine in all host tissues and also in cancer cells . CarnosiConsidering the energetic metabolism in cachectic muscle tissue, the provision of ATP for muscle contraction and activity can be completely altered, diverting this energy to the protein catabolic process, since anabolic capacity in this state is jeopardised . TherefoSome tissues, such as skeletal muscle, have a limited fatty acid synthase activity, which generates cytoplasm malonyl-CoA via acetyl-CoA carboxylase to regulate fatty acid oxidation ,60. On tIn summary, the most significant variations found in our work, such as glutamate, glutamine, glycine, and methylhistidine, associated with succinate and cytidine, led us to point out some specific changes in the initial stage of tumour growth, which may be related to the start of muscle proteolysis and reduced production of energy by the muscle. All these metabolite changes were more expressive in the weanling hosts but they were also found in AW animals , and could also determine the onset of the cachexia state .Some limitations of the present study may be raised for future investigations, especially regarding the translational value. First, the metabolomic extraction process and the technique/platform used here may differ from in some other studies, which could explain some of the different results found in the literature. In addition, the Walker-256 tumour, the experimental model used here, has an exponential growth that leads to a high tumour mass/body weight ratio, unlike in humans. Moreover, this study gave some insights into what happens at different stages of life but cannot predict what happens in paediatric cancer patients—the real translational ages used in this study —as they Female Wistar rats at different ages were obtained from the Animal Facilities of the State University of Campinas, UNICAMP, Brazil. The general guidelines of the United Kingdom Coordinating Committee on Cancer Research  regarding animal welfare were followed. The 21-day-old animals were named “weanlings” (W) and the 90-day-old animals were named “young adults” (A), according to the developmental stages proposed by Sengupta . The exp6 viable cells of the Walker-256 tumour (W) and were euthanised by decapitation at different states of tumour evolution: initial , intermediate , and advanced . The control groups were euthanised after 14 days for the weanling group  and after 21 days for the young adults . After the euthanasia, gastrocnemius muscles and tumours were resected and weighed. Fragments of gastrocnemius muscle were immediately frozen in liquid nitrogen and stored at −80 °C for further metabolomic analysis.The tumour-bearing animals were implanted with 2 × 102 daily) minus the nitrogen excretion through faecal material  and urinary excretion . The diary nitrogen content in the diet, faeces, and urine were measured by using a colorimetric micro-Kjeldahl method. The results are presented as a percentage of mg N2 in 24 h vs. the initial value [From each animal kept in individual metabolic cages, the nitrogen balance refers to nitrogen incorporation by food intake  and sonicated  for 3 min with a 10 s pause between each minute. A cold chloroform/distilled water solution  was then added to the samples. Samples were briefly vortexed and centrifuged at 3000× g for 20 min at 4 °C. The polar phase was collected and dried in a vacuum concentrator . The remaining solid phase was rehydrated in 0.6 mL of a D2O-containing phosphate buffer  and 0.5 mM of TMSP-d4. The solution obtained was added to a 5 mm NMR tube for immediate acquisition.Gastrocnemius muscle samples were processed following Le Belle and colleagues’ protocol . Briefly1H-NMR spectra acquisition was performed using a Varian Inova NMR spectrometer  equipped with a triple resonance probe and operating at a 1H resonance frequency of 500 MHz and a constant temperature of 298 K. In total, 256 free induction decays were collected with 32 K data points over a spectral width of 16 ppm. A 1.5 s relaxation delay was incorporated between scans, during which a continuous water pre-saturation radio frequency field was applied.The After data acquisition, spectroscopic data pre-processing was performed. Manual spectral processing, which included Fourier transformation, phasing correction, baseline correction, water region deletion, shim correction, apodisation (line broadening with lb ~0.3), and referencing control, was applied before the profiling was performed. The identification and quantification of the metabolites were made by computer-assisted manual fitting using Chenomx RMN Suite software . To avoid bias, samples were randomly profiled blindly to the evaluator, and identified metabolites were fitted to each spectrum by the same human operator, resulting in sample profiles consisting of each metabolite. The results were normalised by tissue weight, and the metabolite concentrations are presented in millimoles per mg tissue.p < 0.05 was considered to be significant. The gastrocnemius muscles’ metabolic profile data analyses were performed by two-way ANOVA, followed by post-hoc Tukey’s HSD. Data are expressed as means ± SD, and p < 0.05 was considered to be significant. The statistical analyses were performed using Graph Pad Prism 6.0 software .The morphometric parameters are presented as absolute and relative values. The delta body weight was calculated as  for non-tumour-bearing groups and as —initial body weight) for tumour-bearing groups. The relative values were calculated by dividing the gastrocnemius muscle and tumour weights by each animal’s respective initial body weight. The data analyses were performed by two-way ANOVA, followed by post-hoc Tukey’s honestly significant difference (HSD). Data are expressed as means ± standard deviation (SD) and p < 0.05 adjusted by the false discovery rate (FDR) was considered significant. The statistical analyses were performed using the online MetaboAnalyst 4.0 platform , more specifically the “Pathway Analysis” tool.The metabolic pathways were analysed with a list of metabolites, which were significantly different in the comparisons by two-way ANOVA, followed by post-hoc Tukey’s HSD, by over-representation analysis, using the hypergeometric tests. Data are expressed as match status and regulation (upregulation or downregulation), and


Living things comprise a typical hierarchical and porous medium, and their most fundamental logical architectures are interstitial structures encapsulating parenchymal structures. The recent discovery of the efficient transport mechanisms of interstitial streams has provided a new understanding of these complex activities. The substance transport of interstitial streams follows mesoscopic fluid behavior dynamics, which is intimately associated with material transfer in nanoconfined spaces and a unique signal transmission. Accordingly, the evaluation of interstitial stream transport behavior at the mesoscopic scale is essential. In this review, recent advances in physical and chemical properties, the substance transport model, and the characterization methods of interstitial streams at the mesoscopic scale, as well as the relationships between interstitial streams and disease are summarized. Interstitial stream transport can be used as a basis to fully mine hierarchal behavior in images to expand imaging behavior into an omics field. By starting from the perspective of soft matter, a new understanding can be gained of health and disease and quantitative physical markers for research, clinical diagnosis, and treatment can be provided, as well as prognosis evaluation in complex diseases such as cancer and Alzheimer's disease. This will provide a foundation for the development of medicine of soft matter. The interstitial stream outlines horizontal fluid connection pathway based on the interstitial structure between various organs and tissues. The substance transports of the interstitial stream, including material transfer, energy transduction, and information transmission, serve to enable flat connections between functional structures in the human body and balance the healthy state of the human body. Complex living things show a hierarchical organization from molecules, cells, tissues, organs, and systems to an organism. From the material perspective, living things can be described as being composed of soft matter, such as intracellular stress fibers filled with intracellular fluid at the molecule level, a fibrous network filled with tissue gel in the extracellular matrix at the cellular level, capillaries at the tissue level, multi‐tissue organs and multiphasic media in these tissues at the organ level, and cavities and tissues at the organism level. Among these types of matter, multiphasic fluids in living things show an orderly multiscale spatial flow that determines biological activities. In biological systems, an orderly fluid flow is present in blood vessels and the urinary tract at the millimeter scale and in proton channels at the nanometer scale. These fluids comprise vertical connections in various parts of a living thing. In the circulatory system, the heart pumps blood to various organs and tissues in the human body, constituting vertical connections between organs and tissues. There is reason to believe that different fluid connections are present at all scales between millimeters and nanometers. Various levels of interstitial structure, which are distributed between tissues, constitute a path for fluid connections between these tissues. The concept of interstitial stream was proposed by Han et al. to outline this horizontal fluid connection pathway based on the interstitial structure between various organs and tissues. The substance transports of the interstitial stream, including material transfer, energy transduction, and information transmission, probably serve to enable flat connections between functional structures in living things and form a horizontal bridge between various parts of a living thing to integrate function and behavior. Hence, multiscale fluid behavior in interstitial structures is key for examining and understanding behavioral activities in living things.In 1991, the Nobel laureate and French physicist, P. G. De Gennes,1 prop22.1 Blood is a type of general connective tissue made up mostly of erythrocytes. Mature erythrocytes do not contain a nucleus and are rich in proteins. Plasma and mature erythrocytes can be viewed as a special type of interstitium in blood. When flowing, erythrocytes and plasma can act as a mobile fibrous network complex that is dispersed in blood. When blood remains static, erythrocytes and plasma tend to aggregate, forming a static fibrous network gel structure. Leukocytes and other cells are dispersed in this interstitium. Lymph is the convergence of interstitial fluid, that is, interstitial fluid from the mesoscopic state to macroscopic flow. In this sense, lymph and macromolecules constitute an interstitium. Currently, the tissue embryo model in biomedicine uses cells as the basic structure‐function unit. From this perspective, the interstitium is considered an extracellular matrix structure at the cellular level, and a fibrous network with matrix components in connective tissues at the tissue level.The interstitium, which is present between parenchyma, is ubiquitous in complex living things. Collagen, elastin, and mucopolysaccharides connect to form a non‐liquid system consisting of a fibrous network filled with hydrophilic, porous media. This system is the interstitial structure, and the liquid in the interstitial structure is termed interstitial fluid.2, 4In‐depth examination of past definitions of interstitial structure, connective tissue, loose connective tissue, dense connective tissue, and fascia tends to cause some confusion as even identical structures may have different names. As a result of current bias, the interstitial structure, which should be considered in its entirety, is separated into unrelated parts. Nevertheless, this can be resolved by considering the interstitium from the perspective of soft matter theory. The structure‐behavior‐function unit is the most basic in the human body, which is also the simplest form of fibrous network plus gel. All tangible structure‐function units and groups are bathed in this unit. The presence of hierarchal structures results in efficient interstitial connections. From the high porosity of fibrous networks (such as the extracellular matrix and loose connective tissue) to gradually denser fibrous networks, the matrix gel becomes compressed between single fibrous layers. Multiple layers are ultimately assembled into the fascia, which is compressed into tendons or is wrapped into a fascial space. This systemic interstitial structure, with its flattening connections, provides the most realistic image of biological activities, i.e., a “hierarchical complex fluid‐interstitial connection”. The entire human body is a hierarchical porous medium, in which cells are the characteristic functional structure units, tissues and organs comprise the next level of the functional structure units, and, ultimately, these units are dependent on flat interstitial connections to bond into a complete organism. As interstitial research progresses, the study of interstitial fluid attracts an increasing amount of attention.11 The situation is reversed in dense connective tissue as collagen fibers and elastic fibers are densely arranged such that almost all free water is expelled, leaving water that is immobile and bound to proteins. Multiple fibrous layers  are arranged in different directions to form the fascia, and the free diffusion or directional flow of interstitial fluids is inhibited by this fascia. Loose connective tissues lie between these two extremes as fibers are not densely arranged but are loosely connected to form a porous medium scaffold that is filled with interstitial fluid. In addition to bound and free water, the other components of the interstitial fluid in these tissues mostly show fluid behavior in nanoconfined spaces at the mesoscopic scale.Figure Interstitial fluid is composed primarily of bulk water. Various cells, biological macromolecules, micromolecules, and ions can diffuse through the interstitial fluid or undergo directional flow.12 The have examined interstitial fluid in recent years and have obtained important and inspiring results. Although our understanding of interstitial structures is clearer now, there is insufficient knowledge pertaining to interstitial fluid behavior. As more in‐depth research is conducted on interstitial fluid behavior, a greater understanding of its physiological function and significance in terms of complex diseases can be achieved.According to conventional knowledge, parenchymal structures that confer biological functions are encapsulated by the interstitium. The interstitial structures have been shown to have auxiliary functions such as support, protection, and segmentation, but their physiological and pathological functions and their significance have not received sufficient attention in research to date. Many studies16 hav2.2The free diffusion and flow of cells, molecules, ions, and nanoparticles in interstitial structures is usually narrowly defined as fluid behavior. This type of fluid behavior is intimately associated with material transfer in living things. It has an essential significance for understanding the physiological function of the interstitial structure and using this interstitial structure as a novel drug delivery route. In addition, it has become the focus of recent studies on interstitial fluid. employed the electron microscope to study lymphedema and found that plasticizers can enter micropores in the interstitial structure through the capillary network. Smith et al. were also the first to report the presence of conduction channels between interstitial structure and tissues. These channels have a randomly distributed porous grid‐like structure, and Smith et al. termed the flow paths for materials, energies, and information transport in fluid‐rich tissue as tissue channels. Li et al. employed radionuclide to study its migration trajectory along the meridians, which was closely related to the vascular system but no to the nerves. In addition, Li et al. pointed out that the meridian might be unknown functions of known structures. Zhang et al. found low hydraulic resistance channels in miniature pigs, which was related to interstitial fluid, but the specific anatomical structure and mechanism remained unclear.In 1978, Smith et al.7 empl employed two‐photon imaging to observe fluid transport behavior in the para‐vascular spaces of intracranial blood vessels in mice and found direct evidence of exchange between cerebrospinal fluid and brain interstitial fluid, that scientific interest in research on interstitial fluid was reignited. Nedergaard et al. named this pathway the glymphatic pathway. In subsequent studies, it was found that metabolic micro‐molecules produced in the cranium can enter the circulatory system through this pathway, thereby clearing brain parenchymal waste products. It was thought that the glymphatic pathway replaces the role of the lymphatic system in the brain. In the same year, Yao. et al. simulated the directional interstitial flow under the parallel nature of capillaries conditions and explained that in vivo interstitial fluid flow might constitute the mechanical environment of cells and play a significant role in guiding cell activities. Mediation of mast cells may be the key to qi generation, indicating a close relationship with interstitial fluid.However, it was not until 2012, when Nedergaard et al.10 emp we found that interstitial fluid exists in somatic parts of the human body in the presence of lymphatic vasculature. Our research team first reported that long‐range fluid transport behavior is present in connective tissues in the tunica adventitia of veins, and this long‐distance efficient transport pathway, mediated by porous media at the mesoscopic scale, was termed the interstitial stream. These findings expanded our knowledge on directional transport of interstitial fluid from the brain to the entire body. Further studies found that intervaginal space injection of nanogold particles showed an in vivo biological distribution that is completely different from that of intravenous injection, demonstrating the potential for delivery of nanodrugs through this pathway. In addition, injection of liquid metals through this path can be used for encapsulating, segmentation, and treatment of tumors. Li et al., after injecting fluorescent molecules into fingers in human cadavers, conducted cardiac compressions and observed that a subcutaneous liquid conduction route appeared in the forearm, which entered the intermuscular layer at the upper arm before being traced to the atrial appendage.Unlike the findings of Nedergaard at al.,20 we 2.3 observed oscillations in the friction force between water and carbon nanotubes and showed that these oscillations result from the coupling between confined water molecules and the longitudinal phonon modes of the nanotube. They thought this coupling could enhance the diffusion of water molecules. The interstitial structure is in accordance with the characteristics of a hierarchical‐multiphase‐porous medium. Hence, interstitial fluid displays significantly different behaviors in various mesoscale spaces. For instance, we found that fast molecular transport along a multiphase interface serves as a high‐performance “green pathway” in a micrometer scale hydrophobic fiber network filled with a nanometer scale hydrophilic porous medium. In terms of this hydrophilic fiber network filled with a nanometer‐scale hydrophilic porous medium, we observed an increase of up to 80% in the diffusion coefficient of a fluorescent tracer subject to mechanical force stimulation compared to simple diffusion. However, fluid flowing in blood at the mesoscale performs significantly differently from that at a larger scale. The behavior of blood is often over‐simplified as a homogeneous Newtonian fluid in large blood vessels neglecting the low proportion of interactions between red blood cells and vessel walls. However, blood flowing in micro‐vessels cannot be considered a homogeneous fluid because it contains a high concentration of suspended cells, principally highly deformable red blood cells, whose dimensions are close to blood vessel diameters. Therefore, the ratio of interactions between red blood cells and the vessel endothelial cells is large. The surface effect plays a key role in capillaries, in which the mesoscale endothelial surface layers play a lubricated role to aid the motion of red blood cells.Fluid transport behaviors perform what appears to be magic at the mesoscale. For example, Zheng et al.24 obsFigure  found that the selected transport behavior of ions is established using highly anisotropic nanochannels of a porous anodic alumina membrane.Not only is the performance of liquid transports fascinating, but electromagnetic transmission behavior within the human body is also intriguing. Figure 26 fou Therefore, the substance transports of the interstitial stream have an important significance for understanding the physiological function of the interstitium and are crucial to the diagnosis and treatment of diseases. However, research on the substance transport of the interstitial stream is still phenomenological. A united mathematical‐physical model for the substance transport of the interstitial stream is needed.Material transfer and energy transmission at the mesoscale have been observed. Various physical signals are the carriers of information. Thus, information can also be transported at the mesoscale. The interstitial structure is a typical mesoscale structure. Therefore, we think that the transport behavior of interstitial fluid in the interstitial structure can take three forms, including material transfer, energy transduction, and information transmission. We summarized this as substance transport of interstitial fluid. Studies on the diagnosis and treatment of complex diseases, and the understanding and regulation of the interstitial stream have attracted increasing attention.29 The33.1 However, when the microscopic arrangement of the fibrous scaffold shows some directionality conduction in the interstitial structure can show macroscopic anisotropy. When this is the case, the interstitial fluid is affected by microscopic structural effects, and transport completely differs from macroscopic transport and is termed mesoscopic transport.In addition to interstitial fluid transport behavior being between the two extremes of free transport of bulk water at the macroscopic level and complete transport block in dense interstitial membrane structures, complex fluid state transport in multiscale porous media is also present. This has not been explored in relation to the traditional biological fluids . Without loss of generality, the mixed interstitium can be divided into a fibrous scaffold plus gel complex  and interstitial fluid at the microscopic level. From the analysis in the above section, it can be seen that the conduction coefficient of fluids does not have spatial direction selectivity, i.e., it is isotropic. When the microscopic arrangement of the fibrous scaffold shows a completely random distribution, the overall conduction coefficient of the interstitium is also isotropic.30 How Torquato et al. proposed a valid transport model for anisotropic multiphase media. In order to describe the microscopic characteristics of the interstitial fluid, a set of tensor coefficients An(i) can be used for statistically quantitative characterization of microscopic structural information, which is defined as follows:ϕi represents the volume fraction of the ith group, U represents the unit dyad, t(r⃗)=dr⃗r⃗−r2Ur5, and Sn(i) is the probability function for the nth point in the ith group; details on the parameter Cn(i) are available in a previously published paper. The conduction coefficient for the interstitial fibrous scaffold is λe, the conduction coefficient for the interstitial fluid is λi, the substance transport parameter Λ is a second‐order tensor in the three‐dimensional space, and spatial anisotropy is determined by the microscopic topology of the interstitial structure:B = (X + 2Y)−1(X − Y) and β=x−yx+2y. Under normal circumstances, the substance transport coefficient Λ is a tensor, showing that mesoscopic transport has direction selectivity, i.e., the conduction efficiency is higher in some directions. When the volume fraction of an interstitial component decreases to zero or indicates that the tensor coefficient An(i) in microscopic topological information is isotropic, the substance transport tensor Λ in Equation . The higher the FA, the higher the selectivity for this transport direction. The efficient interstitial stream pathway for interstitial fluid substance transport can be tracked by connecting the efficient transport directions throughout the space.Experiments have proven that the interstitial stream has a long‐distance efficient material transfer function.23 The We extended the idea to encompass the whole body.Our model extended the mathematical‐physical description for liquid materials transport in the interstitial stream to materials, energy, and information transport behavior. A similar idea was used for the brain only.36 We 3.2 Diffusion MRI aims at characterizing the water molecule diffusion of interstitial fluid, which has been used to track nerve fiber bundle interstitial stream pathways. However, interstitial stream imaging is rare. Non‐invasive imaging methods used in other fields have the potential for application in the characterization of substance transport in the interstitial stream.Traditional imaging methods have already elucidated the rudiments of substance transport behavior in interstitial streams. For example, diffusion magnetic resonance imaging (MRI) is currently the only non‐invasive imaging technique that measures the diffusion of water molecules in living tissue.37 DifFigure Flow can be measured by MRI, and corresponding MRI measurement techniques have also been developed for detection of electrical and magnetic characteristics. The newly emerged magneto‐acousto tomography has great potential in conductivity measurements.  can be used to measure flow velocity and direction. In recent years, PC‐MRI‐based 4D flow imaging has undergone rapid development and is widely used for cardiovascular hemodynamic assessment. Analysis of the flow velocity field can also be used to calculate other fluid dynamic parameters, such as pressure gradient and shear force. Davies et al. combined PC flow velocity coding and echo planar imaging sequences to increase the temporal resolution of flow velocity measurements. Electromagnetic imaging: In 2004, Leigh et al. proposed the concept of quantitative magnetic susceptibility imaging. After improvements were made by Haacke et al., this technique could accurately measure the spatial distribution of magnetic susceptibility in the human body. By changing the angle direction between the test sample and the main magnetic field, the anisotropic magnetic susceptibility tensor can be used for imaging. Katscher et al. used the second‐order derivative of the three‐dimensional amplitude and phase distribution of the radiofrequency field in MRI to quantitatively characterize the spatial distribution of the dielectric constant and conductivity in the human body. In recent years, emerging magneto‐acoustic tomography has been used to mutually convert electromagnetic signals and ultrasound signals, which can precisely measure conductivity distribution in organisms.Flow velocity imaging: Phase‐contrast (PC) MRI44 can3.3 first linked the bulk modulus and effective thermal expansion coefficient in isotropic diphasic mixed media. Milton obtained the correlations between the effective dielectric constant, bulk modulus, and shear modulus in two‐component composite materials. Cherkaev and Gibiansky established the relationship between the dielectric constant and magnetic susceptibility. Milton proposed a universal method for establishing correlations among various parameters.Not all parameters of interstitial stream substance transport can be measured with current imaging methods. In addition to flow velocity, diffusion, electrical, and magnetic imaging, direct non‐invasive in vivo measurement and imaging are still not possible for other transport parameters . In addition, existing electrical properties imaging cannot be used to characterize the spatial anisotropy of the dielectric constant and conductivity. On the other hand, measuring magnetic susceptibility tensor requires multiple changes in the placement of the sample and has many limitations, particularly when used for imaging of the human body. In physics and engineering, the successful use of easily measured physical parameters to indirectly characterize physical parameters (that are difficult to measure) is also exceedingly difficult and problematic. Levin55 fir extended the parameter relationship to anisotropic two‐component media and used the tensor coefficient to characterize the topological characteristics of the microscopic structure. In 2001, Tuch et al. proposed using the diffusion tensor to indirectly characterize the conductivity tensor. They were the first to apply the association attributes of two parameters in imaging measurements. This method is currently used in brain conductivity distribution assessment before transcranial current brain stimulation. Frau‐Pascual et al. used this method to construct an electrical conduction model of brain structure connections. The idea was that association attributes can play an important role in substance transport imaging of interstitial stream. Based on the tensor model of interstitial stream substance transport, by using existing diffusion, flow, and electromagnetic imaging methods and constructing quantitative relationships between association attributes, we can indirectly characterize values and spatial anisotropy of transport parameters that are usually difficult to directly measure, such as thermal conductivity, acoustic conductivity, bulk modulus, and elastic modulus. This can provide comprehensive technical support for interstitial stream substance transport behavior studies.As mentioned in Section 33 ext4 Many studies found that blood flow and perfusion behavior in the brain and functional and structural changes in blood vessels are important risk factors for many neurodegenerative diseases. Hence, MRI perfusion imaging is expected to provide imaging markers for early prediction of Alzheimer's disease. In addition to cerebro‐cardiovascular disease, blood flow in tumors is also an extremely important reference for cancer diagnosis. For example, dynamic contrast‐enhanced MRI is used to analyze and compare the spatiotemporal patterns of contrast agent entry/exit in tumor tissues and is used clinically for cancer detection, diagnosis, staging, and treatment response evaluation. Diffusion tensor imaging can be used to measure the diffusion tensor of water molecules in cerebral white matter, thereby tracking and imaging nerve fiber bundles. This method has been applied in the clinical diagnosis of Alzheimer's disease, demyelination, and stroke. In addition, information on force transmission in patients has also been applied in diagnoses for many years. For example, ultrasound elastography is already widely used in the diagnoses and treatment of liver, breast, and thyroid disorders and has achieved satisfactory results.With the emerging dominance of complex diseases such as cerebro‐cardiovascular disease, malignancy, and degenerative disease, it is difficult for the structure‐function‐based biomedical model to guide development of modern medicine, and there is a need for reorganization and a new understanding of the nature of biological activities. Currently, various types of information on fluid behavior in the human body are used for diagnosing disease. For example, in cerebro‐cardiovascular disease, MRI can provide images of different phases in the cardiac cycle to obtain the cardiac motion pattern and calculate local strain and related cardiac wall motion parameters, which are used to assess overall cardiac function and diagnosis of myocardial diseases.60 Man Patients with COPD have a two‐ to three‐fold higher probability of being diagnosed with IBD. With developments in research on gut and lung disease correlations, the concept of the gut‐lung axis has been proposed. Similarly, there is also a large number of studies on the correlation between the gut and brain and between kidney disease and cardiovascular disease. Although many studies have examined the molecular mechanisms between diseases, the relationship between immune functions in these distal organ and tissue diseases has not been completely elucidated. Visceral fat tissue contains a large amount of interstitial structures. Studies have reported that intestinal bowel diseases and lung diseases can both change the inflammation status of visceral fat tissue. These results imply that interstitial streams are an essential link between multiple organs. Understanding the relationships between distant tissues throughout the whole body is crucial for the diagnosis and treatment of complex diseases.The synergy of the whole body should be considered when treating complex diseases. Many studies have pointed out that there are significant correlations between different organ and tissue diseases, such as between chronic obstructive pulmonary disease (COPD) and intestinal bowel disease (IBD).65 Pat The aforementioned reports concluded that distal tissues in living things can form a long‐distance, direct, and efficient connection through the interstitial stream that is present throughout the body and is mutually connected. The fascial space at the macroscopic scale and the interstitial structure at the mesoscopic scale can transport a substance containing large amounts of materials, energies, and information, which provide a material basis for efficient and coordinated communication between various organs and tissues. Therefore, there is reason to believe that the interstitial stream enables flat connections between functional structures in living things through material, energy, and information connections and forms a horizontal bridge between various parts of the organism to integrate function and behavior. Herein, our tensor model of interstitial stream substance transport will significantly contribute to the completion of a full characterization of fluid transport methods, thus, facilitating the diagnosis and treatment of diseases.Overly focusing on structure and ignoring fluid transport information, means that the synergy of the whole body may be underestimated. After discovering the long‐distance‐transport interstitial stream, our research group conducted a series of further studies. For example, preclinical studies on a mouse breast carcinoma in situ model found that intervaginal space injection of liquid metal can be transported to within the vicinity of the carcinoma in situ along the interstitial stream pathway.9 The The examples above demonstrate the positive roles of fluid behavioral information in disease diagnosis. Many methods for characterizing material, energy, and information transport used in clinical practice and research studies can be used to characterize interstitial stream substance transport behavior. The response pattern of biological soft matter to the external environment is non‐linear. Therefore, many static markers cannot wholly describe the status of tissues and organs. However, the studies described above acquired only a single or several markers and used superficial statistical differences to differentiate diseases. They also did not consider constructing links between characterization parameters and physical status. Our group used fluid mechanics as a base to establish links between behavioral information and biological status. We then proposed cell modulus measurement and dynamic fitting of pathological sections. and the cellular diffusion coefficient, we proposed a multiparametric method for characterizing the physical characteristics of cells. This method can distinguish between different types of cells and can also be used to classify and identify healthy cells and cancer cells of the same type. Compared with using Young's modulus alone to distinguish between healthy and cancer cells, this method is greatly superior. Figure As a basic unit vital to living things, mechanical model analysis of single cells is an extremely active and challenging research domain. To describe and analyze the physical behavior of cells, researchers have developed many physical models using different perspectives. Based on the porous medium model, we analyzed intracellular fluid phase behavior and improved the data extraction method for the cellular Young's modulus to obtain a cell modulus measurement method closer to the cellular scaffold modulus. By integrating intracellular apparent viscosity70 and Therefore, we proposed a dynamic fitting method for pathological section information and obtained the disease progression trend by fitting geometric pathological markers. This enabled a more accurate evaluation of the progress of patients with colon cancer.Pathological diagnosis is currently the gold standard for disease diagnosis. We found that there are also considerable differences in the prognosis for different Tumor‐Node‐Metastasis (TNM) pathological stages. Our group started by using topographical and mechanical effects to analyze the relationship between the curvature of adenocarcinoma tissues and late‐stage invasion. We found that the greater the curvature of the tumor gland tissues, the greater the malignancy and the poorer the prognosis.75 TheThe method mentioned above was used to construct relationships between behavioral information and disease state and prognosis progression trends at the cellular and tissue levels. The method was then used to propose a relevant mechanical and fluid‐related parametric model for prediction, which converted static medical information into dynamic behavioral descriptions. This method provided the idea for selecting the most informative type of information that can best reflect biological behavioral activities among numerous types of behavioral information. It provided a direction for constructing a relationship model that analyzed the substance transport behavioral information of the interstitial stream and biological status. In addition, as living things themselves naturally possess specificity, it is impossible to employ conventional statistical markers  to completely describe the substance transport of interstitial stream spatial distribution in the entire lesion. Therefore, we should integrate information on the structure and fluids of living things to expand the development of imaging behavior omics, particularly the physical/chemical/biological behavior of the interstitial stream. This would be a breakthrough in the development of appropriate new medical imaging and characterization methods and the construction of a mathematical model on imaging behavioral characteristics and disease, which would provide theoretical and technical support for accurate diagnosis and personalized treatment.5 More efforts are needed to depict interstitial stream pathways in the human body. In addition, the dynamic mechanism underlying the interstitial stream is still unclear. A large number of studies have shown that matter performs unique transfer characteristics in nanoconfined space. The multiphase and multiscale fibrous gel network in the human body contains abundant micro‐nanometer scale confined space. The force resulting from the evaporation of lung and sweat glands on the surface may be one of these dynamic sources. Muscular movement and vascular pulsation may also be dynamic sources for the interstitial stream. Hence the behavior of interstitial fluid substance transport in the human body is worth exploring.Studies on the relationship between interstitial stream substance transport and human health are still in their infancy. Enormous problems and challenges remain to be solved. The physiological implications of interstitial stream transport behaviors are critical. Interstitial stream pathways are the basis of studies in this field. At present, only a few interstitial stream pathways between limbs, organs, and brains have been elucidated.23 Mor The role of the interstitial stream material transport in this process is very intriguing. In addition, the biological effects of interstitial stream energy transport on the immune system in the interstitial stream pathway are also worth studying. Mechanical action from interstitial fluids can stimulate the immune system. For instance, fasciitis in the interstitial stream pathway is an immune‐related disease, and the energy transport behavior of interstitial streams is likely to play a significant role in its development. Moreover, physical quantities can carry information and produce significant biological effects in the path of the interstitial stream, thus affecting the pathological process of human disease. For example, a warm‐sensitive neuron in the preoptic area can respond to thermo‐sensory signals. In conclusion, the substance transport behavior of the interstitial stream is closely related to the physiological states of human diseases. Clarifying the biological significance of the substance transport behavior of the interstitial stream will substantially promote medical science development.The relationship between the occurrence, progression, and prognosis of a disease and the transport of interstitial stream substances under pathological conditions is critical. For example, in invasion and metastasis, tumor‐derived exosomes can induce liver pre‐metastatic niche formation to increase the metastatic liver burden.77 The Many physical characteristics of the transport are difficult to characterize. Moreover, only a single direction can be detected, making it difficult to characterize the physical characteristics of the anisotropy. It is key that translational medicine develops a characterization method for medical imaging of physical quantities, detects more types of interstitial stream transport behaviors, and detects the transport characteristic direction of corresponding physical quantities. Magnetic‐acoustic‐electronic imaging, MRI, ultrasonic imaging, and Terahertz imaging have great potential for uncovering the substance transport behavior of the interstitial stream. To extend the above tools to measuring more transport parameters and tracking interstitial stream pathways, more work should be done to complete the tensor model of interstitial stream substance transport. After obtaining information on interstitial stream transmission behavior, it will be a significant challenge to rationally use this information for disease diagnosis and treatment. However, no perfect method for analysis of information on the substance transport behaviors of the interstitial stream has been proposed at present. Establishing an approach to bridge the relationship between interstitial stream substance transport behavior and disease state is critical to improving its medical translation.Developing methods of imaging characterization are key to transforming research results on interstitial stream substance transport into medical applications. However, state of the art imaging characterization methods can only characterize part of the interstitial stream substance transport, such as fluid flow and diffusion, electrical conduction, and elasticity.64 Man6Living things are typically composed of soft matter in a logical structure composed of various interstitial levels that are distributed among parenchymal tissues. The interstitial stream connects material, energy, and information to enable flat connections between functional structures in living things and form a horizontal bridge between various parts within the organism to integrate function and behavior. The tensor conduction model can describe the substance transport behavior of the interstitial stream in complex living things. It can provide a new way of understanding the complex activities within life forms, and potentially track interstitial stream pathways. The breakthrough of using the physical/chemical/biological behaviors of interstitial streams and integrating biologically complex fluid behavior allows the existing acquisition method for most static medical information to be converted to dynamic behavioral descriptions, such as the cellular modulus, dynamic fitting of pathological sections, ultrasound elastography, and MRI. This can be used to develop a new multiscale behavior‐related medical imaging and characterization method, to construct a mathematical model on imaging behavioral characteristics and disease, to provide theoretical and technical support for accurate diagnosis and personalized treatment, and to expand imaging behavioral omics. Imaging and characterizing substance transport behavior of interstitial streams in living bodies and organizing the links between various tissues and organs can inform systematic and quantitative research and provide a clinical application tool to diagnose complex diseases and formulate personalized physical therapies.7In the last century, the invention of antibiotics and vaccines and the emergence of various advanced medical equipment has allowed genomics and biomedical research to gradually move from the body, organ, tissue, and cell level to the molecular level. This has had a massive impact on human health, and the healthcare industry and medical science and technology have improved dramatically. This has laid the foundation of a health view, disease view, and diagnosis and treatment view of structure‐function coupling. Although our understanding of diseases has deepened, and diagnosis and treatment of clinical diseases have undergone rapid development, the benefits of these medical developments on human health seem to be limited. With the emerging dominance of complex diseases such as cerebro‐cardiovascular disease, malignancy, and degenerative disease, the structure‐function‐based biomedical model overly focuses on the tangible structure, ignores dynamic information, and relies mostly on static objective markers. Its standards originate from statistical analysis of big data and the subjective judgment of physicians, which usually separates patients and diseases. Therefore, inaccurate disease definition causes a bias in treatment logic. Modern medicine should reference theories that conform to biological behavioral activities to improve disease definition, thereby guiding treatment logic to overcome the doctrine and limitations of the biomedical model and so become more effective. Starting from the soft matter theory, focusing on multiscale biological fluid behavior; re‐describing biological activities; conducting in‐depth research on the structure‐behavior‐function mechanism; employing methods such as medical imaging, clinical treatment, biological materials, new drug development, and non‐drug treatments; and compensating for shortcomings in actual clinical activities of the current structure‐function‐based “hard matter” thinking in mainstream medicine can provide a basis for the development of a new medical model, i.e., a PEO‐medicine (People‐Excitement‐Obedience Medicine) that is represented by the medicine of soft matter.The authors declare no conflict of interest.