The discovery of Sanal flow choking in the cardiovascular‐system calls for multidisciplinary and global action to develop innovative treatments and to develop new drugs to negate the risk of asymptomatic‐cardiovascular‐diseases. Herein, it is shown that when blood‐pressure‐ratio (BPR) reaches the lower‐critical‐hemorrhage‐index (LCHI) internal‐flow‐choking and shock wave generation can occur in the cardiovascular‐system, with sudden expansion/divergence/vasospasm or bifurcation regions, without prejudice to the percutaneous‐coronary‐intervention (PCI). Analytical findings reveal that the relatively high and the low blood‐viscosity are cardiovascular‐risk factors. In vitro studies have shown that nitrogen, oxygen, and carbon dioxide gases are dominant in fresh blood samples of humans/guinea pigs at a temperature range of 98.6–104 F. An in silico study demonstrated the Sanal flow choking phenomenon leading to shock‐wave generation and pressure‐overshoot in the cardiovascular‐system. It has been established that disproportionate blood‐thinning treatment increases the risk of the internal‐flow‐choking due to the enhanced boundary‐layer‐blockage‐factor, resulting from an increase in flow‐turbulence level in the cardiovascular‐system, caused by an increase in Reynolds number as a consequence of low blood‐viscosity. The cardiovascular‐risk can be diminished by concurrently lessening the viscosity of biofluid/blood and flow‐turbulence by raising the thermal‐tolerance‐level in terms of blood‐heat‐capacity‐ratio (BHCR) and/or by decreasing the systolic‐to‐diastolic blood‐pressure‐ratio. It has been shown that at a critical systolic‐to‐diastolic blood‐pressure‐ratio, the internal‐flow‐choking  can occur anywhere in the cardiovascular‐system with or without a plaque or stent. The uneven usage of blood‐thinning drugs increases cardiovascular‐risk because low blood‐viscosity is a risk‐factor for internal‐flow‐choking causing the shock‐wave generation at a critical‐pressure‐ratio. Admittedly, heart failure (HF) is the cardiovascular epidemic of the 21st century. The ischemic heart disease or coronary heart disease (CHD) refers to atherosclerosis of the coronary arteries, where the deposit of plaques cause reduced blood flow and/or arterial blockage. Cardiovascular disease (CVD) refers to all types of diseases that affect the heart or blood vessels, including CHD. Although there has been significant advancement in the diagnosis, prognosis, treatment, and prevention of heart failure with reduced ejection fraction, the morbidity and mortality are still extensive. This is particularly true due to the Covid‐19 pandemic (www.escardio.org). An ejection fraction is a blood flow measurement in percentage (%), specifying how much blood the left ventricle pumps out with each contraction. An ejection fraction measurement under 40% may be an indication of heart failure or cardiomyopathy. An ejection fraction from 41%–49% may be considered as “borderline” cases having the history of stroke (memory effect). A normal heart's ejection fraction may be between 50%–70%. An ejection fraction value higher than 75% generally indicates hypertrophic cardiomyopathy (HCM), which could affect people of any age. HCM is reported as a cause of acute heart failure particularly in young people, including young athletes. It is important to note that though all these percentage demarcations of the ejection fraction are meaningful for the diagnosis it was not supported by any closed‐form analytical model for taking an authentic conclusion on the desirable blood flow percentage for forecasting the risk of acute‐heart‐failure (AHF) and furthering medical management in an individual subject. The European Society of Cardiology (ESC) reported (2020) that subjects with cardiovascular‐risk factors and proven CVD denote an exposed population when agonizing from the Covid‐19. ESC also added that subjects with cardiac injury in the perspective of Covid‐19 have an enhanced risk of illness and demise (www.escardio.org). In light of the discovery of Sanal flow choking in the cardiovascular system, the thermal tolerance of the Covid‐19 patients’ blood needs to be examined in terms of biofluid/blood heat capacity ratio (BHCR) for the risk assessment of the cardiovascular disease.Discovery of Sanal flow choking (PMCID: PMC7267099)1 in t ischemic heart disease (IHD) and asymptomatic hemorrhage(AH)/stroke are the world's biggest killers. The truly popular consequence of management with the blood‐thinning‐drug, causing to lower blood viscosity is bleeding and very frequently asymptomatic hemorrhage and acute heart failure happens without any preceding symptoms. Milton Packer reported (2018) that acute heart failure is an event and not an illness and put forward a coherent claim for multidisciplinary research and a paradigm shift in thinking in the therapeutic drug development with a focus on the chemistry of drugs. This is particularly inevitable at this juncture due to the Covid‐19 pandemic and associated cardiovascular risk. V. R. S. Kumar et al. discovered (2018) that such a transient episode leading to asymptomatic hemorrhage and acute heart failure is due to the Sanal flow choking (due to the boundary layer blockage (BLB) induced convergent‐divergent (CD) nozzle flow effect) and/or biofluid choking (due to the plaque induced CD nozzle flow effect or due to vasospasm) at a critical systolic‐to‐diastolic blood pressure ratio (BPR)  due to the compressible viscous flow effect. An internal flow choking due to blood viscosity variations and turbulence in CVS leads to cavitation, shock wave generation, and transient pressure‐spike. Note that internal flow choking could happen in vasospasm, vasa vasorum, and/or nanoscale tubes too. When the pressure of the nanofluid/non‐continuum‐flows increases, average‐mean‐free‐path decreases and thus, the Knudsen number reduces leading to a no‐slip boundary condition with compressible viscous flow effect. The Sanal flow choking is a compressible viscous flow effect creating a physical situation of sonic‐fluid‐throat in the CVS at a critical systolic‐to‐diastolic blood pressure ratio (SBP/DBP), due to the BLB.AHF is reported as the biggest killer globally over the centuries. Very frequently, fatal AHF happens without prior indications of coronary artery obstruction (angina). According to the world health organization (WHO),6 isch The BLB factor depends on the Mach number, viscosity of biofluid/blood, BHCR, and the flow turbulence level. The Sanal‐flow‐choking could happen in any blood vessel without an iota of the symptom of plaque. Note that Equation . The HI highlights (see Equation (Cp) and the other thermo‐physical properties of blood at the risk of internal flow choking leading to asymptomatic hemorrhage and acute heart failure.We discovered through theoretical studies that, at the creeping inflow conditions, the blood/biofluid flow in the circulatory system with the sudden expansion/divergent/vasospasm/expansion valves/bifurcation duct, with or without any plaque or stent, could predispose to supersonic flow condition leading to the shock wave generation and pressure‐overshoot due to the phenomenon of internal flow choking  an unchoked‐fluid‐flow condition HI < 1) must be satisfied throughout the circulatory system. It could be achieved by maintaining hemorrhage index (HI) always lower than one or the BPR always lower than the lower‐critical‐hemorrhage‐index (LCHI), which is dictated by the lowest value of the BHCR of evolved gases in the cardiovascular‐system (see Equation ). For in1 causEquation  shows th must be Equation  are two Equation  that a dCp) and the specific heat of blood at constant volume (Cv), estimated using the Differential Scanning Calorimeter – Perkin Elmer DSC 8000.The LCHI is predicted (see Equation ) using t there were no authentic conclusions to support whether hypertension or hypotension is of more risk with regards to asymptomatic hemorrhage and acute heart failure. V. R. S. Kumar et al. reported that an AHF could occur in both hypertension or hypotension patients because the controlling parameter of this event is the BPR. In brief, attaining a critical BPR is considered as a risk factor for asymptomatic hemorrhage and acute heart failure. Therefore, at the threshold of the internal flow choking condition, a minor oscillation in BPR for both hyper and hypo subjects is likely to aggravate the risk of heart failure. In light of the discovery of flow choking in blood vessels, the classic definition of the hypertension causing cardiovascular risk is largely arbitrary (SBP ≥140 and/or DBP ≥90 mmHg). The prevailing cardiovascular risk data remains challenging owing to the fact that internal flow choking could occur in both hypertension or hypotension subjects once BPR reaches LCHI /ACC/HRS, a new generation blood‐thinning drug, non‐vitamin K oral anticoagulants (NOACs), is now suggested as the favored substitute to warfarin for reducing the risk of stroke allied with atrial fibrillation (AFib). Note that large swings in BPR create periodic choking and unchoking phenomena causing atrial fibrillation or an irregular heartbeat (arrhythmia). This multidisciplinary review paper aims to highlight the fundamental cause(s) of asymptomatic cardiovascular disease and propose possible solutions for reducing the risk of asymptomatic hemorrhage and acute heart failure.There are two main types of blood thinners namely, anticoagulants such as heparin or warfarin and antiplatelet drugs, such as aspirin to prevent blood cells from clumping together to form a clot. According to a focused update19 and The use of antiplatelet is frequently in grouping or as a substitute to anticoagulant. INR is utilized to decide the coagulation trend of blood and is necessary for blood thinning medication . In general, for a healthy person the estimated normal range of INR is about one and it is reported that the INR is from 2.0 to 3.5 for subjects under anticoagulant therapy. An enhanced INR implies a high tendency of bleeding, whereas the lower INR is a warning of the high risk of having a thrombotic event in patients who are on anticoagulant therapy. Accordingly, anticoagulant and antiplatelet are exercised interchangeably, there is a conventional laboratory index, namely, INR for regular checking to assess contraindication to and/or need for anticoagulant; but none for antiplatelet. Therefore, this issue is worth addressing in terms of variations in whole blood viscosity and the altered turbulence level due to the blood thinning medication and/or seasonal effects. Note that the analytical prediction of the Sanal flow choking is a breakthrough in biological science, which creates a radical change in the diagnostic sciences of asymptomatic vascular diseases because the various causes of the Sanal flow choking are complementary with all the established concepts in medical sciences. The concepts of Sanal flow choking is well correlated herein with the existing theories and concepts in the biological sciences for finding possible solutions for reducing the risk of internal flow choking leading to shock wave generation causing the asymptomatic hemorrhage and acute heart failure.International normalized ratio (INR) is the chosen trial of option for subjects taking vitamin K antagonists (VKA), which helps to predict the risk of bleeding or the coagulation status of the subjects. Subjects using oral anticoagulants are essential to monitor INR to regulate the VKA quantities because these differ among subjects.20 The as blood viscosity changes due to fluid force and blood thinning medications. Viscosity variations are dependent on the shear rate or shear rate history of the blood/biofluid, which could vary due to seasonal effects too. Blood temperature decreases during the winter season resulting in an increase in blood viscosity and the inverse effect happens during the summer season. It corroborates that the BLB factor causing the Sanal flow choking would alter due to the blood viscosity variations as a consequence of the blood‐thinning medication and/or the seasonal effects. Indeed, BLB induced internal flow choking is more prone during the winter season than the summer season due to the higher blood viscosity at the relatively low blood temperature. It leads us to say that the risks of biofluid choking leading to asymptomatic hemorrhage and acute heart failure would be high during the winter than in the summer season, which is corroborating with the literature data. It is important to note that blood‐thinning medication will increase the Reynolds number, which produces a high turbulence level creating an enhanced BLB factor causing an early flow choking. All these deliberations lead to corroborate that relatively high blood viscosity and low blood viscosity are risk factors for an early internal flow choking in cardiovascular system (CVS) causing asymptomatic stroke/hemorrhage and acute heart failure, which correlates with the established index, namely, the INR. Therefore, the real effect of viscosity on internal flow choking in CVS needs to be established to take preventive strategies for reducing the risk of asymptomatic hemorrhage and acute heart failure. On this rationale, it is essential, rather needed, perhaps inevitable to declare a condition for prohibiting the internal flow choking in the CVS, in terms of viscosity, density, Reynolds number, BHCR, BPR, ejection fraction, and stenosis (vessel geometry), which we have attempted herein through the closed‐form analytical methodology.Admittedly, whole blood viscosity is popularly the one of Virchow's triad, which is a recognized concept that pronounces the three widely found types of causes that are believed to interpose to thrombosis causing cardiovascular complications, namely, hypercoagulability, hemodynamic changes , and endothelial injury/dysfunction. Further, it is well known that blood is a non‐Newtonian fluid23 as  narrated that decreasing the blood viscosity and concurrently reducing the turbulence level are the crucial missions to prevent acute heart failure. As stated earlier these two missions conflict with each other. Rongjia Tao further reported that the only recognized technique to decrease the blood viscosity is to take a drug, such as aspirin. Note that using medicine to reduce the blood viscosity only makes the turbulence worse and increases the chances of cavitation and biofluid choking because the BLB factor will be more for the turbulent flow than the laminar flow. The flow turbulence increases the deficit of energy in the form of friction, which increases the BLB in blood vessels and generates heat and augments the internal energy causing a decrease in the heat‐capacity‐ratio of blood/biofluid, which is vulnerable to an early flow choking in the cardiovascular system. Based on the above findings we established herein that the lopsided blood‐thinning drugs increase the risk of internal flow choking triggering acute heart failure, which supports the established laboratory index, namely, the INR. More specifically, an overdose of drugs for blood‐thinning medication increases the Reynolds number leading to the high turbulence level in the vessel and as a result the laminar flow could be disturbed and becomes turbulent causing an early internal flow choking causing a transient sharp pressure‐spike due to the generation of shock waves at the creeping inflow condition without any iota of symptoms of the plaque in an artery with sudden expansion/divergence/vasospasm/bifurcation  of bleeding while taking blood‐thinning drugs and propose possible solutions for reducing the risk of internal flow choking causing asymptomatic hemorrhage and acute heart failure. In a nutshell, the proof of the concept of Sanal flow choking in cardiovascular‐system leading to asymptomatic hemorrhage and acute heart failure is established herein through closed‐form analytical methodology, in vitro study and in silico modeling, which are briefly reviewed in the subsequent sections.Rongjia Tao25 nar2di), the corresponding inflow Mach number (M), the axial Mach number , and the BHCR, which is derived from compressible flow theory.The BLB in the blood vessels can be influenced by the variations in the blood viscosity and the BHCR of the flowing gas/nano plasma. The Equation  correlatp = Cv). That is patently not true as the human blood specific volume (or density) does change with temperature or pressure. At the Sanal‐flow‐choking condition, the creeping flow will get accelerated in a uniform cross‐sectional area duct due to the area blockage caused by the boundary‐layer‐displacement‐thickness . The 3D BLB at the Sanal‐flow‐choking condition (Maxis = 1) for diabatic flows  is given in The previous researchers, in general, assumed that the human blood is an incompressible fluid  nozzle shape or vasospasm  always less than one in the cardiovascular‐system. Mach number depends on the local velocity  and local velocity of sound. Equations Alocal), local velocity , (BHCR)lowest, and the DBP. In high risk subjects (BPR close to LCHI or hemorrhage index close to 1.0) a minor swing in the BPR predisposes to the choking and the unchoking phenomena leading to arrhythmia. Most heart valve problems involve the aortic and mitral valves, possibly because of its geometric shape similar to a convergent‐divergent (CD) duct flow passage. Note that the internal‐flow‐choking could create unusual pressure‐overshoot in vessels with vasospasm, divergent/bifurcation regions, which increases memory effects (stroke history) leading to aneurysm and/or artery tear in the subsequent stroke.The blockage factor in the blood vessels could change due to the seasonal effects as a consequence of the differences in blood viscosity.18 If  This is particularly true and inevitable for predicting the aneurysm and hemorrhagic‐stroke when the propagation of waves through such arteries, with diabatic flows (flow involves transfer of heat), having the vessel‐walls with thermoviscoelastic properties. Interestingly, the “memory effect,”  is the prominent characteristic of any viscoelastic material. Herein, we defined the memory effect as the stroke history wherein the current state of stress and past stroke histories determine the mechanical response of the material, namely, the onsite relaxation modulus of the blood vessels including vasa vasorum and capillaries. Therefore, an accurate and a priori knowledge of the combined effect of the rheology of biofluid and the thermoviscoelastic response of the vessels is inevitable for predicting an aneurysm and other asymptomatic cardiovascular diseases using the fluid‐structural interactive code calibrated with the credible Sanal flow choking condition. For establishing the proof of the concept, we have demonstrated herein the Sanal flow choking and shockwave generation at a critical pressure ratio in a viscoelastic tube with vasospasm using air as the working fluid at the atmospheric exit flow condition . Further discussion of valve problems, aneurysm, and arrhythmia is beyond the scope of this review article.It is abundantly clear from the physiological literature that the arterial wall material is viscoelastic and a priori knowledge of memory effects of such viscoelastic materials at multi‐axial stress conditions during the seasonal changes is necessary for understanding the behavior of the arterial tree better.53 Thi3Table Figure 2 −m/z = 28, O2 −m/z = 32, CO2 −m/z = 44, Ar −m/z = 40, an unknown composite gas(CG) −m/z = 28.5), from the blood samples of four different healthy human beings and one healthy male Guinea pig four weeks old, during the hyphenated technique at a blood temperature of 40 °C (104 F). Figure 2) gas evolved as a function of both time and temperature obtained from blood sample tests of healthy subjects (human beings and a Guinea pig). We used a quadrupole mass spectrometer of Perkin Elmer make SQ8T with Electron Multiplier as the detector. During our comprehensive in vitro studies, we have noticed that the gases evolved from the fresh blood sample depends on the blood temperature, heating rate, blood group, age, and the blood pressure (BP) value. It is evident from Figures 2 is consistently the dominant gas for human beings at a large temperature range whereas nitrogen (N2) gas is dominant in the blood sample of the Guinea pig. In light of Figure 2) gas (BHCR = 1.4) generated within the thermal tolerance level. We found that there are variations in the heat capacity of blood samples collected in three different Vacutainers of the same subjects. We have noticed that the anticoagulant reduces the BHCR and is susceptible to an early internal flow choking in blood vessels, including vasa vasorum, causing a high risk of asymptomatic hemorrhage, and acute heart failure. It is well known that the most common side effect of treatment with anticoagulant medicine is bleeding. Therefore, until the discovery of new drugs for increasing the BHCR, the physician should calculate and prescribe the doses of anticoagulant drug for each and every patient based on the clinical data of the individual subjects using the closed‐form analytical models presented herein  – Perkin Elmer DSC 8000. Please note that the ethical approval is not required by the national legislation of Indian union for conducting the blood sample test of healthy subjects. inea pig.79 In of 40 °C 04 F. Figquations –5c)) fo) foTable2 is found to be higher in the animal whereas in human beings CO2 is found to be higher. The BHCR of N2 is 1.4 and that of CO2 is 1.289. At this thermal loading condition, the animal artery gets choked only at a BPR of 1.8929 and the human artery gets an early choking at a BPR of 1.8257. Therefore, we concluded that the thermal tolerance level of the healthy Guinea pig is higher and the cardiovascular risk is lower than for a human being under identical conditions. On this rationale, increasing the thermal tolerance level in terms of BHCR of the human being is an important factor for reducing the risk of acute‐heart failure (AHF) due to the Covid‐19 or otherwise.It is crystal clear from Figure e higher.1 The 4 We could demonstrate the shock wave generation and pressure overshoot at the downstream region of an artery with a divergent region  shape of the streamtube. Herein, we provide the proof of the concept of fluid‐throat persuaded flow choking in the cardiovascular system. For establishing this concept authoritatively, we have presented an infallible closed‐form analytical model  using a validated flow solver.10 We odel see  for pred5 the real occurrence of AHF remains poorly understood, largely for the reason that it was an under diagnosis condition. Now the real cause of an AHF comes to the foreground. In patients with a recent history of the embolic stroke of undetermined source, dabigatran was found to be not superior to aspirin in preventing recurrent stroke. Based on a three clinical trials report, John W. McEvoy highlighted that aspirin for the primary prevention of cardiovascular disease has become increasingly hard to defend, however, the physician recommends that it is reasonable to continue aspirin with low‐dose for the subject, Mr. Evans, a 72‐year‐old man with blood pressure 130/72 with a diagnosis of external hemorrhoids. On the contrary, another physician, Sigrun Halvorsen recommends to the same subject, Mr. Evans, to stop taking aspirin because the absolute benefit associated with aspirin in this elderly man is small due to the increase in the risk of major bleeding. In brief, we recommended Mr. Evans should always maintain his systolic‐to‐diastolic BPR lower than LCHI through drugs or otherwise for an extended healthy life.Although the diagnostic sciences have been advanced significantly during the last eight decades, until the dissemination of this article and connected articles,83 the revealed that blood plasma has a pronounced viscoelastic behavior. Many studies have been carried out and reported worldwide on the variations of blood viscosity and seasonal changes on blood pressure (BP) causing several cardiovascular diseases. The viscoelastic material possesses a characteristic that can be referred to as a “memory effect,” . It means that the material response is not only determined by the current state of stress, but is also determined by all of the past stress histories. Therefore, an accurate and a priori knowledge of the combined effect of rheology of biofluid and the thermoviscoelastic response of the vessels (the memory effect/stroke history) is inevitable for predicting acute heart failure using the fluid‐structural interactive code. All the findings reported and reviewed herein are complementary with the existing literature and clinical data on variations of blood viscosity and seasonal changes on blood pressure (BP) causing several cardiovascular diseases.Viscosity of blood is directly related to the number of red blood cells (hematocrit). Blood plasma has been considered a Newtonian fluid for decades but through experiments Brust et al.22 revAn internal flow choking in the cardiovascular system (CVS) leads to shock wave generation and pressure overshoot at various physical situations  of blood reduces the risk of acute‐heart failure, which is an indisputable physical condition for prohibiting asymptomatic cardiovascular diseases ), th), th5)),59 It quations –(5)).We recognized that the internal flow choking, leading to shock wave generation and the transient pressure spike in a blood vessel, is the fundamental cause of asymptomatic hemorrhage and acute heart failure. Now the precipitating factor for the plaque rupture has come to the foreground. We concluded that biofluid choking (due to plaque induced blockage or due to vasospasm) and the Sanal‐flow‐choking (due to BLB) could occur anywhere in the circulatory circuit when BPR reaches LCHI. The BLB‐factor depends on the BHCR, flow Mach number, the biofluid viscosity, and turbulence, which could alter due to seasonal changes, variations in lipoprotein and other contributing factors. The greater the reduction in low‐density lipoprotein (LDL) cholesterol, the lower the risk of stroke. It is important to note that all the clinical findings are corroborative of the models presented herein for predicting the condition of prohibiting the asymptomatic cardiovascular diseases. The shock wave and cavitation could disrupt an atherosclerotic plaque or coronary artery wall. The cavitation is quite noisy and can be sufficiently violent to physically damage valves, arteries, and blood vessels.All these studies lead to an authentic conclusion that the BHCR, the critical BPR, and memory effect (stroke history) are the key deciding factors for hemorrhagic stroke and acute heart failure. We concluded that high BHCR reduces the risk of asymptomatic hemorrhage and acute heart failure and that for a healthy‐life all human beings and animals with the high systolic‐to‐diastolic BPR (hypertension/hypotension subjects) invariably have to maintain high BHCR. In a nutshell, the discovery of the biofluid/Sanal‐flow‐choking is a paradigm shift in the diagnostic sciences of coronary artery disease (CAD) and peripheral artery disease (PAD).Through closed‐form analytical models (see Equations –5)) we ) we 5)) 2), oxygen (O2), carbon dioxide (CO2), and argon (Ar) gases are predominant in the fresh blood samples of healthy subjects at a temperature range of 37–40 °C (98.6–104 F), which enhances the chances of internal flow choking (with or without any coronary artery stent) leading to pressure‐overshoot and acute heart failure in Covid‐19 patients. We detected that CO2 gas generation is comparatively and persistently higher in healthy human beings than the healthy male Guinea pig. In vitro results show that BHCR of fresh blood samples are higher than those collected in three different Vacutainers of the same subjects. The thermal tolerance level of healthy Guinea‐pig is found to be greater and the cardiovascular risk is lesser than in the healthy human being. Analytical findings reveal , BHCR, DBP, Reynolds number, and the local velocity . It is evident from these mathematical models that at a constant vessel cross sectional area and DBP decrease in BHCR and an increase in Reynolds number jointly or individually, increase the possibilities of internal flow choking. Apparently,  are  are 5) a11 It quations , and  an incrquations  and 2a) It isCp) of blood samples of healthy subjects  taken from the EDTA and Lithium Heparin tubes were found to be 32.789% and 33.1594% lower, respectively, than the fresh samples of the same healthy subjects tested within 5 min of collection. It proves conclusively that drugs with anticoagulant properties reduce the BHCR and increase the risk of internal flow choking leading to the asymptomatic cardiovascular diseases. Through hyphenated techniques we could detect four known gases, namely, N2, O2, CO2, and Ar in the fresh blood samples of healthy subjects of human beings and an animal at 98.6–104° F. We observed that, carbon dioxide (CO2), the gas with the lowest HCR is relatively and consistently higher in the healthy males than the healthy male Guinea pig of four weeks old  – Perkin Elmer DSC 8000, reveals that blood is a compressible fluid. There are deviations found in the BHCR of fresh samples of blood collected in different Vacutainers for the same healthy subjects. The specific heat capacity  are the major risk factors deciding the possibilities for the aneurysm, asymptomatic hemorrhage, and acute heart failure in all subjects. The analytical and the in vitro procedures described herein will play a key role in the future medical sciences for the prediction and negation of aneurysm, arrhythmia, hemorrhagic stroke, and myocardial infarction (MI) a priori, with or without symptoms of the plaque on the artery walls through new therapies, new drug discoveries, medical procedures, or diagnostics, namely, the estimation of the BHCR.We presumed that thrombophilia, gas embolism, the blood glucose, and other property variations of blood could alter the BHCR of individual subjects, which could alter LCHI. We comprehended that in addition to the gene editing, within the framework of the pathophysiological constraints of individual subjects, the transfusion of blood with high HCR could negate the risk factor of the asymptomatic hemorrhage and acute heart failure in high‐risk subjects owing to the fact that it creates less chances of internal flow choking in the cardiovascular system.5.2Large randomized blood sample tests for BHCR, estimation along with the BPR measurement, adequately in all seasons in all blood groups, across the globe are needed for discovering new drugs capable of increasing the BHCR and/or decreasing the BPR in all seasons for reducing the risk of internal flow choking in all subjects. Note that the internal flow choking leads to acute myocardial infarction (MI) and asymptomatic strokes of various types. Therefore, BHCR of the Covid‐19 patients’ needs to be estimated for predicting the risk of a cardiovascular epidemic.Randomized tests for thermo‐gravimetric, thermolysis, and speciation analyses of blood samples of all subjects, in all blood groups, in all geographical regions of the globe in all seasons are envisaged to check the thermal tolerance level and the cardiovascular risk of each and every subject.This seminal review article opens a new avenue of research in biological and material sciences for accurately estimating memory effects for pinpointing the locations and conditions of plaque/artery rupture a priori through the analytical, in silico, in vitro, in situ or in vivo studies. The 3D printing model test, in situ or in vivo studies, are recommended for examining memory effects and the altered variations of the on‐site relaxation modulus of vessels. The in vitro estimation of the chemical and elemental species of each and every subject along with the blockage factor estimation are recommended for forecasting the risk of an early flow choking due to seasonal changes.Animal models, without pain and mortality, are recommended for the parametric study of internal flow choking, aneurysm, arrhythmia, asymptomatic hemorrhage, and acute heart failure before proceeding for therapies in human being for lowering the risk of acute MI and improving clinical outcomes. The breakthrough concept of internal flow choking  phenomenon expedites the discovery of new diagnostic tools and treatments through our multidisciplinary collaboration.5.3Mostly, in the cardiovascular system blood flow is considered as laminar. When taking blood thinning drugs, the whole blood viscosity reduces and as a consequence the Reynolds number rises and the laminar flow could be disordered and converted to turbulent. The flow turbulence enhances the deficit of energy in the type of friction, which increases the BLB in the vessels and generates heat and augments the internal energy affecting a reduction in BHCR, which is corroborated with in vitro results. Additionally, turbulence enhances the perfusion pressure essential to push the blood flow. We concluded that the cardiovascular treatment should be targeted based on BPR, instead of blood pressure levels alone, in chronic heart failure patients.We concluded that a single anticoagulant drug capable of suppressing the turbulence level and enhancing the BHCR, or a companion medicine along with the traditional blood‐thinning medications is predestined for meeting the conflicting requirements  of all the subjects for reducing the risk of asymptomatic hemorrhage and acute heart failure. In high risk subjects  a slight oscillation in the BPR predisposes to the choking and the unchoking phenomena, which could lead to arrhythmia and memory effect. In a nutshell, we have proved conclusively that the high‐BHCR reduces the risk of internal flow choking as dictated by Equation , which i1 We c this manuscript is submitted to the global community for discovering a brilliant chemical formula urgently for increasing the thermal tolerance level of all human beings worldwide after due consideration of the pathophysiological constraints of individual subjects for clinical trials for prohibiting the cardiovascular epidemic in Covid‐19 patients and also for the general categories through proper medical management.Briefly, we concluded that the risk of internal flow choking heading to asymptomatic hemorrhage and acute heart failure could be decreased by concurrently reducing blood viscosity and turbulence by enhancing the BHCR or reducing the BPR. This manuscript discloses new insights into the cardiovascular epidemic of the 21st century and the associated disease process that allow researchers to design drugs through nanotechnology with a proper chemical composition worldwide for increasing the BHCR and for reducing the risk of a cardiovascular epidemic due to the Covid‐19 pandemic. Note that when the pressure of the nanofluid increases, the average mean free path decreases and thus, the Knudsen number reduces leading to a no‐slip boundary condition with a compressible viscous flow effect. The Sanal‐flow‐choking is a compressible viscous flow effect, which is established as the flow choking caused by the BLB at the creeping inflow condition at a critical pressure ratio. The Sanal‐flow‐choking is an undesirable phenomenon, which could cause asymptomatic stroke and/or acute heart failure in Covid‐19 patients. The sporadic internal flow choking, due to significant fluctuations in BPR, heading to transient pressure‐overshoots created throughout a life‐span in the cardiovascular system, creates vessel walls which are stiffer due to memory effects (stroke history). Such physical situations in any of the viscoelastic vessels are prone to rupture in the subsequent internal flow choking and shock wave development. We concluded that the risk of internal flow choking leading to asymptomatic hemorrhage and acute heart failure could be reduced by concurrently reducing blood viscosity and turbulence by enhancing the BHCR  or decreasing the BPR. In light of the recent guidance of the European Society of Cardiology,41 thiThe scientific objective of this study and review was to discover the correlation between the thermal tolerance level in terms of BHCR, the BPR, blood viscosity, ejection fraction, and the cardiovascular risk leading to asymptomatic hemorrhage and acute heart failure, which we could achieve herein. We concluded that designing a precise blood thinning regimen is vital for attaining the desired therapeutic efficacy and negating undesirable flow choking leading to acute‐heart failure. The uneven usage of blood‐thinning drugs enhances the risk of the internal flow choking owing to the enhanced BLB due to turbulence. For a healthy‐life all subjects with high‐BPR inevitably have high‐BHCR for reducing the risk of the internal flow choking  triggering acute heart failure due to shock wave generation. We corroborated that, the acute heart failure is a transient episode and not an illness.8, 9 and thermal level monitoring in high risk patients in the diagnosis and preventive management of asymptomatic cardiovascular diseases. Continuous blood pressure and thermal level measurement could be done in a more pragmatic way by using a wearable BP monitor with a temperature sensor in the modern form of a wristwatch. Analytical methods such as machine learning could definitely enhance accuracy and advance daily wearable device‐based diagnoses. Of late (2020) Amrith Mariappan et al. reported that the silicon powder obtained from the recycling of space debris could be used for producing feigned soil for fostering pharmaceutical flora in the International Space Station (ISS) to discover scarce‐drugs for increasing the BHCR for high‐endurance health care management. M. D. Delp et al. highlighted that Apollo lunar astronauts exhibit higher cardiovascular disease mortality. It is known that cardiovascular risk is higher in astronauts/cosmonauts but the fundamental cause of such risk was unknown to medical science until the dissemination of this article and our connected articles. The beauty and novelty of the internal choking phenomenon, discovered in the cardiovascular system and nanoscale system, reviewed herein is that the causes and effects of the Sanal flow choking in cardiovascular system satisfy all the clinical findings world‐wide  pertaining to the risk factors of asymptomatic cardiovascular diseases reported over the centuries.Briefly, we could establish herein that at the creeping inflow condition there are possibilities of the generation of shock waves followed by transient pressure‐overshoot in the cardiovascular system having convergent‐divergent (CD) duct (due to plaque deposit or BLB) flow region immediately after the internal flow choking . The discovery of the Sanal flow choking phenomena calls for a continuous ambulatory blood pressure (BP)71 and6Acute heart failure (AHF) is the biggest killer world‐wide. Through analytical, in vitro, and in silico studies the authors demonstrated that a disproportionate blood thinning treatment increases the threat of asymptomatic cardiovascular disease (CVD). For maintaining a healthy life all subjects  with high‐BPR inevitably have blood with high‐heat capacity ratio for reducing the risk of internal flow choking and associated asymptomatic CVD. Drugs capable of enhancing the thermal tolerance could diminish the cardiovascular‐risk in all subjects including the Covid‐19 patients. The authors found out that at a critical BPR the Sanal flow choking occurs in the cardiovascular‐system with sudden expansion/divergence/vasospasm/bifurcation regions leading to the generation of shock waves and a transient sharp pressure‐spike causing asymptomatic‐hemorrhage (AH) and acute heart failure (AHF). This review article sheds light for exploring new avenues in biological science for discovering new blood‐thinning drugs for reducing the risk of internal flow choking causing AH and AHF in the Covid‐19 patients and also in the general category.The authors declare no conflict of interest.V.R.S.K.: Conceptualization, analytical modeling, manuscript drafting; S.K.C.: In vitro conceptualization, manuscript editing; P.K.R.: In vitro conceptualization, manuscript editing; R.S.B.: In vitro and data generation; N.C.: In vitro, in silico, and project support, V.S.: Modeling and simulation support, A.S.: In silico simulation support, C.O.: Resources.Supporting InformationClick here for additional data file.Supplemental Video 1Click here for additional data file.


S‐adenosyl‐l‐methionine (SAM), which experiences transcriptional and posttranslational control of its synthesising enzymes (SAM synthetase), as well as the metabolic flux through the adjacent Yang cycle. Ethylene biosynthesis continues from SAM by two dedicated enzymes: 1‐aminocyclopropane‐1‐carboxylic (ACC) synthase (ACS) and ACC oxidase (ACO). Although the transcriptional dynamics of ACS and ACO have been well documented, the first transcription factors that control ACS and ACO expression have only recently been discovered. Both ACS and ACO display a type‐specific posttranslational regulation that controls protein stability and activity. The nonproteinogenic amino acid ACC also shows a tight level of control through conjugation and translocation. Different players in ACC conjugation and transport have been identified over the years, however their molecular regulation and biological significance is unclear, yet relevant, as ACC can also signal independently of ethylene. In this review, we bring together historical reports and the latest findings on the complex regulation of the ethylene biosynthesis pathway in plants.The gaseous plant hormone ethylene is produced by a fairly simple two‐step biosynthesis route. Despite this pathway’s simplicity, recent molecular and genetic studies have revealed that the regulation of ethylene biosynthesis is far more complex and occurs at different layers. Ethylene production is intimately linked with the homeostasis of its general precursor  These new insights add weight to the importance of a careful regulation of ACC homeostasis due to its dual role in controlling ethylene biosynthesis and ACC signalling.The volatile hormone ethylene is a major regulator of many developmental and physiological responses in plants (Abeles S‐adenosyl‐l‐methionine (SAM) is converted to ACC and 5′‐methylthioadenosine (MTA) by the enzyme ACC synthase (ACS)   as the active‐site co‐factor, and 2OG and molecular oxygen as co‐substrates for activity. ACO is unique within this family because it uses ascorbate, not 2OG, as a co‐substrate  ACS genes was found to be necessary for proper navigation of the transition from autoinhibitory (system I) to autocatalytic (system II) ethylene production during tomato fruit ripening , inducing its expression , also known as methionine adenosyltransferase (MAT). Other metabolic pathways also influence the SAM pool Fig. , which pSAMS genes were shown to be regulated at the transcriptional level by developmental cues and hormonal signalling , senescence of carnation (Dianthus caryophyllus) petals and climacteric fruit ripening of tomato and peach (Prunus persica)  directly inhibits expression of SlSAMS1, providing evidence of a direct link between auxin signalling and SAM biosynthesis  was shown to inactivate SAMS1 by S‐nitrosylation  discs  during submergence  are not ethylene regulated, and a mtk mutant does not result in lower ethylene levels in dark grown seedlings  seedlings  leaves  hypocotyls  seeds  germination  plants  after an application with the synthetic auxin 1‐naphthylacetic acid  plants only observed phloem‐mediated ACC, and not MACC transport  seedlings that were treated with exogenous ACC. Altogether, more research is needed to create clarity about long‐distance MACC transport and the existence of dedicated transporters.MACC is likely to be synthesised in the cytosol, and can accumulate in the vacuole  have been identified, of which only GGT1 and GGT2 appear to be catalytically active  which showed a reduced ACC uptake when fed neutral amino acids , harbours a functional disruption of the amino acid transporter LYSINE HISTIDINE TRANSPORTER1 (LHT1)  was shown to have a specialised role in d‐amino acid metabolism  and ACC (MACC) levels were higher in dat1 mutants (Suarez et al., d‐amino acids and conjugate ACC, but also that there are still unknown biochemical links that could explain the d‐amino acid stimulated ethylene production in plants.In general, ACS and ACO gene expression have been unravelled, with many more likely to be uncovered. Both enzymes also show a complex posttranslational regulation, of which the stability and dimerisation of ACS has been thoroughly studied. However, the role and biological significance of the redox‐mediated posttranslational regulation of ACO remains elusive. At the metabolic level, it is clear that SAM levels and the activity of the Yang cycle play an important role in sustaining ethylene production. The pleiotropy of other SAM‐demanding metabolic processes and the multistep recycling pathway of MTA, create many additional layers of complexity that influence the regulation of SAM homeostasis. On top of that, our knowledge of the regulation of the ACC pool is far from clear. Despite the identification of three ACC conjugates and two ACC transporters, the molecular regulation of these ACC‐dependent steps are unknown and could advance the field. The emerging role of ACC as an ethylene‐independent growth regulator only strengthens the belief that ACC levels are tightly controlled. The dual function of ACC in signalling and ethylene biosynthesis will certainly boost novel discoveries that will shed more light on ACC formation, conjugation, degradation and localisation.Despite the fact that the ethylene biosynthesis pathway is a simple two‐step pathway and was discovered 4 decades ago, its regulation is less well understood. Recently the identity of several transcription factors that control JP, JV‐H and BVDP performed the literature research and wrote the paper. JP and JV‐H contributed equally to this work.


Acral lentiginous melanoma is a histological subtype of cutaneous melanoma that occurs in the glabrous skin of the palms, soles and the nail unit. Although in some countries, particularly in Latin America, Africa and Asia, it represents the most frequently diagnosed subtype of the disease, it only represents a small proportion of melanoma cases in European‐descent populations, which is partially why it has not been studied to the same extent as other forms of melanoma. As a result, its unique genomic drivers remain comparatively poorly explored, as well as its causes, with current evidence supporting a UV‐independent path to tumorigenesis. In this review, we discuss current knowledge of the aetiology and diagnostic criteria of acral lentiginous melanoma, as well as its epidemiological and histopathological characteristics. We also describe what is known about the genomic landscape of this disease and review the available biological models to explore potential therapeutic targets. ALM arises in acral locations, specifically in palms, soles and the nail unit. The word “lentiginous” refers to its radial growth phase, which appears before the tumour starts invading the dermis. The terms “lentiginous” and “acral” might not be used always together, and could cause some confusion even among pathologists and clinicians. Before we delve deeper into its characteristics, some definitions are in order: as ALM is the most common histopathological subtype of melanoma that arises in acral sites, some authors use acral melanoma and ALM as interchangeable terms  is seen on the proximal nail‐fold skin  or 6 (CDK6), and whose activity is required for G1/S transition. This cell distribution may explain the characteristic parallel ridge pattern of acral melanoma , immune excluded or inflamed phenotype. Their cellular and molecular properties are determinants of melanoma progression and therapeutic response , which encodes a type III receptor tyrosine kinase that can stimulate cell growth, division, survival and migration; Cyclin D1 (CCND1) and cyclin‐dependent kinase 4 (CDK4), which encode a cyclin and a kinase that when bound to each other promote the transition from G1 to S phase; cyclin‐dependent kinase inhibitor 2A (CDKN2A), which encodes for two proteins: p16(INK4A) and p14(ARF), the latter of which helps stabilize TP53; telomerase (TERT), encoding an enzyme crucial for telomere maintenance; and aurora kinase A (AURKA), which is involved in regulation of cell cycle progression by playing critical roles in mitosis  samples, Hayward et al.  identifiKIT, NRAS proto‐oncogene (NRAS) and the BRAF proto‐oncogene (BRAF), respectively, and noted that their results were similar to those described in other Korean and Asian populations, but that mutation rates were lower than those observed in other studies. As NRAS and BRAF are among the most commonly mutated genes in other melanoma subtypes due to their crucial roles in triggering the mitogen‐activated protein kinase (MAPK) pathway, Shim et al.  mutations resulting in the activation of the MAPK pathway seems to be lower in ALM than in other subtypes of melanoma  , which are extremely large amplicons comprising >100 Mb of genomic material and present in high copy number (often in more than 50 copies)  platforms have been developed, but few ALM specimens were included in the collections. Krepler et al.  and GarmUntil 2012, only seven ALM cell lines derived from primary and metastatic lesions from different laboratories had been described  decreased cell viability of two acral melanoma cell lines with copy‐number gain and promoter mutations on TERT, whereas no effect was observed in normal melanocytes, suggesting the potential of TERT as a therapeutic target in ALM  and WM3211 (L576P)  (Kong et al., CDK4 gain/CDKN2A loss. Furthermore, activation of CDK4 pathway, in the case of acral melanoma patients achieved via CCND1 copy‐number gains, was associated with response to PD‐1 blockade (Yu et al., Oncogenic activation of the CDK4 pathway through copy‐number gains in 7ALM is a complex disease that appears to have both weak germline genetic risk factors and an environmental component, potentially trauma associated with mechanical injury, involved in its aetiology. Germline components may have a role in cell cycle regulation, given the observation that these patients may have an increased risk of other types of cancer, or in melanocyte development, but larger analyses such as genome‐wide association studies are needed to establish whether there is a true genetic signal and what functional role it may have.Diagnosis of ALM is difficult, being easily confused with other dermatological conditions, and because of this, it is usually diagnosed at later stages compared with other melanoma subtypes. However, whether this late diagnosis causes its poorer prognosis or whether ALM is inherently biologically more aggressive remains to be addressed. In this regard, dermoscopy is widely regarded as being the best method to diagnose promptly ALM, providing a considerable improvement in diagnostic accuracy over other examination methods.Acral lentiginous melanoma also appears to be a different disease compared with CM, given the microenvironment differences between glabrous and non‐glabrous skin, the embryonic origin of acral melanocytes and its immune compartment. This may be reflected in the large differences in the genomic landscape of CM and ALM, with the latter having a much lower number of mutations but a higher number of large chromosomal aberrations. The mutational landscape is also strikingly different, with CM being dominated by a UV‐induced signature but ALM displaying age‐associated signatures. Definitely, large‐scale ALM studies are necessary for establishing genomic drivers and mutational signatures, and more functional analyses are needed to address possible aetiological factors.Some ALM disease models are available, mainly in the form of PDX models and cell lines, but these are still scarce and have not been analysed in great depth. However, their study has already highlighted palbociclib as a possible agent in treating ALM patients with aberrations in the CDK4 pathway, which highlights the power of these kinds of preclinical studies and calls for more research for this subtype of melanoma. Given the strikingly low number of studies on this disease when compared to CM and that it is the most common form of the disease in some countries in Latin America, Africa and Asia, we truly believe it is about time we shift our focus to these regions of the world.None declared.


A 40‐year‐old man with bilateral hilar lymphadenopathy in chest X‐ray and the λ‐sign in gallium‐67 scintigraphy was subsequently diagnosed with systemic sarcoidosis according to the findings of bronchoalveolar lavage and histopathological examinations of transbronchial lung biopsies. Identifying the λ‐sign could be a valuable clue to the early diagnosis of sarcoidosis. The λ‐sign strongly suggests the diagnosis of sarcoidosis because all reported patients with the λ‐sign were subsequently diagnosed as having sarcoidosis. Identifying the λ‐sign with gallium‐67 scintigraphy could be a valuable clue to the early diagnosis of sarcoidosis. He had neither respiratory symptoms nor visual disturbances. His physical examination findings revealed no abnormality other than tenderness in both ankle joints and nodules in both iridocorneal angles. Blood examinations revealed normal serum calcium and angiotensin‐1‐converting enzyme levels, with no autoantibodies indicating autoimmune diseases. While chest X‐rays showed bilateral hilar lymphadenopathy, contrast‐enhanced thoracic computed tomography revealed hilar lymphadenopathy and enlarged lymph nodes in the mediastinum and at S5 in the right lung field Figure . The patThe λ‐sign strongly suggests the diagnosis of sarcoidosis because all reported patients with the λ‐sign were subsequently diagnosed as having sarcoidosis.None declared.YH: involved in the conception of the study, in the literature search and drafting the study, and clinical care of the patient. MT: involved in the conception of the study, and in the literature search and drafting the manuscript. MF: involved in the literature search and drafting the study. SY: involved in the conception of the study and revising the manuscript.The patient gave permission for the publication of this case report. This manuscript conforms to the provisions of the Declaration of Helsinki in 1995 (as revised in Brazil 2013).


Pygoscelis adeliae. Understanding the prevalence and nature of density dependence for this species is important because it is considered a sentinel species reflecting the impacts of fisheries and environmental change over large spatial scales in the Southern Ocean, but the presence of density dependence could introduce uncertainty in this role. Using data on population growth and indices of resource availability for seven regional Adélie penguin populations located along the East Antarctic coastline, we find compelling evidence that population growth is constrained at some locations by the amount of breeding habitat available to individuals. Locations with low breeding habitat availability had reduced population growth rates, higher overall occupancy rates, and higher occupancy of steeper slopes that are sparsely occupied or avoided at other locations. Our results are consistent with evolutionary models of avian breeding habitat selection where individuals search for high‐quality nest sites to maximize fitness returns and subsequently occupy poorer habitat as population density increases. Alternate explanations invoking competition for food were not supported by the available evidence, but strong conclusions on food‐related density dependence were constrained by the paucity of food availability data over the large spatial scales of this region. Our study highlights the importance of incorporating nonconstant conditions of species–environment relationships into predictive models of species distributions and population dynamics, and provides guidance for improved monitoring of fisheries and climate change impacts in the Southern Ocean.Density‐dependent regulation is an important process in spatio‐temporal population dynamics because it can alter the effects of synchronizing processes operating over large spatial scales. Most frequently, populations are regulated by density dependence when higher density leads to reduced individual fitness and population growth, but inverse density dependence can also occur when small populations are subject to higher extinction risks. We investigate whether density‐dependent regulation influences population growth for the Antarctic breeding Adélie penguin  Using data on population growth and indices of resource availability for seven regional Adélie penguin populations located along the East Antarctic coastline, we find compelling evidence that population growth is constrained at some locations by the amount of breeding habitat available to individuals. Locations with low breeding habitat availability had reduced population growth rates, higher overall occupancy rates, and higher occupancy of steeper slopes that are sparsely occupied or avoided at other locations. Alternate explanations invoking competition for food were not supported by the available evidence, but strong conclusions on food‐related density dependence are constrained by the paucity of food availability data over the large spatial scales of this region Most frFor seabird species, the focal group here, life‐history characteristics including geographically separated or patchy breeding habitat, high coloniality, high philopatry, and central place foraging may result in within‐patch dynamics such as density dependence being a driving or constraining force on population dynamics. Processes that regulate seabird population dynamics can occur on land where they breed or in the ocean where they forage through, for example, habitat availability and competition for food, respectively. Evolutionary models of avian breeding habitat selection predict that when habitat quality is spatially heterogeneous and individuals search for high‐quality habitat to maximize their fitness, individuals will occupy the best nest sites first in a preemptive manner to maximize their fitness returns , and compiled estimates of Adélie penguin and flying seabird populations breeding in each region from the published literature.2.3The amount of food available for individual breeding penguins is a function of the total amount of food present in their foraging range and the level of competition for that food by conspecifics or other species. To derive an index of food availability in each regional penguin population, we divided the total primary productivity in the nearest polynya by the biomass of potential avian competitors breeding in the region. We calculated this index using Adélie penguin biomass only to reflect potential intraspecific competition and also using the combined biomass of all seabird species to reflect intra‐ and interspecific competition. We used biomass rather than population size in the calculation to account for the differing body sizes of penguins and flying seabird species , and therefore their food requirements.2) to give the area of unoccupied potential habitat available for population growth, and (c) dividing this area by the Adélie penguin breeding population size in the first breeding season of the population time series to estimate per capita unoccupied potential breeding area. In contrast to the food availability index, we did not consider flying seabirds as potential competitors with Adélie penguins for breeding habitat because their breeding habitat preferences differ substantially :We used an information‐theoretic approach to assess the level of support for three increasingly complex candidate models Figure a of densa across resource availabilities;Candidate 1: density dependence absent across the range of measured resource availabilities, represented by the null model:r from a minimum level b at rate c, andCandidate 2: density dependence present across the full range of measured resource availabilities, represented by the linear model:d is the maximum rate of decrease that occurs in the absence of a resource, e is a constant describing the difference between d and the maximum rate at which a population can increase, and f is the demographic efficiency of a population indexing how quickly pgr changes from being negative to positive as a resource increases , ∆AICc values were calculated as the difference between each model's AICc value and the minimum AICc, and the models were ranked by their ∆AICc values and Akaike weights. Models with ∆AICc ≤ 2 were considered to be strongly plausible, 3 ≤ ∆AICc ≤ 7 considerably less plausible, and ∆AICc ≥ 7 improbable  using R  were used to model the probability of a plot being occupied as a function of region (factor) and slope (continuous variable). First‐ and second‐order slope terms were considered to assess for linearity versus curvilinearity in occupancy–region–slope relationships. An information‐theoretic approach was used to select the most parsimonious models from a set of seven models ranging from a null model of constant occupation to a global model including region, slope, slope3The seven regional Adélie penguin breeding populations are widely distributed along the East Antarctic coastline, vary in size by over two orders of magnitude, and have population growth rates ranging from −0.01% to 2.45% per annum Figure .3.1Thalassoica antarctica which breed on the steep slopes  than elsewhere  at 28 m2 of unoccupied habitat per breeding pair. In contrast, we found no evidence in support of density‐dependent population growth at the regional scale in response to food availability. In scenarios of both potential intraspecific competition only and intra‐ and interspecific competition combined, the null model was a more parsimonious fit to the data than the linear model, and nonlinear models failed to converge  than occurred at the regional level. Nevertheless, the results support the conclusion that density‐dependent population growth in response to low breeding habitat availability also occurs at the local level . Combined, these results are consistent with an ideal despotic distribution model where individuals search for high‐quality nest sites in a preemptive manner and subsequently occupy poorer habitat  as population density increases .The lack of evidence for food‐related density dependence could be explained in a number of ways. Most obviously, it could be that prey in the foraging range of the regional Adélie penguin breeding populations included in this study is superabundant relative to the size of penguin and seabird breeding populations. Dehnhard , for exaOur demonstration of density‐dependent population regulation for Adélie penguins in East Antarctic matches similar conclusions from studies in the Ross Sea and Antarctic Peninsula regions (Che‐Castaldo et al., In response to growing concern for how a future changing environment will affect biota worldwide (Walther et al., By demonstrating that processes operating in the terrestrial environment can constrain Adélie penguin population growth in some regions and local sites, our study highlights the potential for terrestrial processes to mask or confound marine influences on Adélie penguin population dynamics. This casts some caution on the often cited role of Adélie penguin populations as “sentinels” or “indicators” of fishery and climate change impacts on Southern Ocean marine environments Agnew, , and sugThere are no competing interests related to this work.Both authors contributed to all stages of the work. Click here for additional data file.


Reports of crizotinib‐induced pleural effusion in non‐small cell lung cancer (NSCLC) are limited. A 35‐year‐old Japanese woman was diagnosed with ROS1‐rearranged lung adenocarcinoma . Crizotinib was administered as first‐line therapy, and the primary and mediastinal hilar lymph node metastases rapidly shrank. On the fourth day of treatment, chest X‐ray demonstrated contralateral pleural effusion. On the 41st day of treatment, crizotinib was discontinued because of grade 3 neutropenia. Examination including surgical thoracoscopy did not reveal causative findings, and the continued cessation of drug administration enabled the right pleural effusion to decrease gradually and disappear, suggesting that this event was a side effect of crizotinib. The disease did not progress even though the drug was withdrawn for more than one year. In conclusion, crizotinib was considered to cause pleural effusion as an adverse event in a case of ROS1‐rearranged lung adenocarcinoma with a complete response. ROS1 rearrangement has been estimated to be present in 1% to 2% of patients with non‐small cell lung cancer (NSCLC).Pleural disorder is one of the clinical phenotypes of drug‐induced lung injury. Although pleural effusion and pleurisy are listed as adverse events for many drugs, they are rarely observed in clinical practice. This report describes a case of ROS1‐rearranged lung adenocarcinoma exhibiting contralateral pleural effusion caused by crizotinib.A 35‐year‐old Japanese woman was referred to our hospital for evaluation of a mass in the left lower lung field Fig  with a cCrizotinib was introduced as the first‐line therapy (250 mg twice daily). The primary lesion and mediastinal hilar lymph node metastases both shrank rapidly. However, right pleural effusion was observed on chest X‐ray on the fourth day of treatment Fig . The rigTo the best of our knowledge, this is the first report of ROS1‐rearranged lung adenocarcinoma exhibiting pleural effusion caused by crizotinib with a complete response.A diffuse alveolar damage (DAD) patternCrizotinib has inhibitory activity against CYP3A4 and may increase the blood concentration of other drugs. In this case, although the patient had been taking other medications , it is unlikely that they were the causative agents because there have been no reports of pleural effusion caused by these drugs and none whose metabolism is completely dependent on CYP3A4 were included. As the pleural effusion decreased and disappeared after the cessation of crizotinib, it was thought to be the causative agent. However, the involvement of concomitant medications was unable to be excluded because the pleural effusion began to decrease after withdrawing crizotinib and these drugs were subsequently discontinued as the patient's condition improved.et al.Regarding the mechanism of pleural effusion, Gemma In addition, a stable course without recurrence for more than one year after the discontinuation of crizotinib is considered to be markedly rare. According to a previous clinical study,In conclusion, crizotinib was considered to cause pleural effusion as an adverse event in a patient with ROS1‐rearranged lung adenocarcinoma.The authors have no conflicts of interest to declare.


Fast and widespread diagnosis is crucial to fighting against the outbreak of COVID‐19. This work surveys the landscape of available and emerging biosensor technologies for COVID‐19 testing. Molecular diagnostic assays based on quantitative reverse transcription polymerase chain reaction are used in most clinical laboratories. However, the COVID‐19 pandemic has overwhelmed testing capacity and motivated the development of fast point‐of‐care tests and the adoption of isothermal DNA amplification. Antigenic and serological rapid tests based on lateral‐flow immunoassays suffer from low sensitivity. Advanced digital systems enhance performance at the expense of speed and the need for large equipment. Emerging technologies, including CRISPR gene‐editing tools, benefit from high sensitivity and specificity of molecular diagnostics and the easy use of lateral‐flow assays. DNA sequencing and sample pooling strategies are highlighted to bring out the full capacity of the available biosensor technologies and accelerate mass testing. Biosensors for COVID‐19 testing. The landscape of molecular diagnostics for infectious diseases is evolving rapidly to respond to the COVID‐19 outbreak. The sensitivity, specificity and speed of the tests vary depending on the biomarker , sample type (swab or blood) and detection method. Emerging diagnostic tools aim to circumvent roadblocks encountered at each step. The development of tests for SARS took about six months.Unreported infections (mostly asymptomatic or mild cases) increased the number of cases around the worldThe focus of this work is how to detect SARS‐CoV‐2 efficiently on a large scale and with high sensitivity. Figure 22.1E and N genes.Genetic tests use molecular diagnostic assays to detect the presence of viral RNA specific to SARS‐CoV‐2. National laboratories and companies around the world have developed different primers and probes addressing various regions of the viral genome. For example, the CDC in the USA addresses three targets in the nucleocapsid N gene.Every genetic testing protocol follows analogous steps, including sample preparation, RNA extraction, transcription of RNA into complementary DNA (cDNA), amplification of DNA and read‐out. Figure Sample collection: A swab is taken from the nose or throat of the potentially infected individual  is an alternative to PCR that is gaining traction in many point‐of‐care diagnostics devices. Both PCR and isothermal amplification are discussed in the next sections.Signal read‐out: Amplification and read‐out occur simultaneously in qRT‐PCR systems. This is achieved by using fluorescent probes or intercalating dyes, which require bulky, expensive thermal cyclers with embedded fluorescent lamps and detectors. To miniaturise and reduce the cost of the device, alternative read‐out technologies use bead arrays, lateral‐flow assays or electrochemical sensors. Among these innovations, CRISPR‐Cas‐based and DNA sequencing‐based diagnostics stand out, which combine several of the technologies outlined above with innovative amplification and read‐out schemes.2.2qRT‐PCR is the primary tool to diagnose COVID‐19. It requires a forward primer to start DNA synthesis, a backward primer and a fluorescent probe, together with reverse transcriptase and DNA polymerase (responsible for DNA replication). In a single or two‐step RT‐PCR, RNA is converted first into complementary DNA Figure c, and thThe ideal diagnostic test has both high sensitivity (true positive rate) and specificity (true negative rate). The sensitivity is reported together with the limit of detection (LoD). The LoD sets the lowest concentration of SARS‐CoV‐2 RNA that can be detected by the RT‐PCR test, which is determined by detecting the presence of the viral RNA in at least 95 % of the cases. For COVID‐19 assays, the LoD can reach levels lower than 10 genome copies per reaction (0.5 cp/μL).The RT‐PCR test is only indicative of whether the virus is present at the time the test is taken. It neither rules out whether the patient was infected in the past‐and therefore might have developed immunity‐nor that the patient is at an early infection stage and will show symptoms in the future.2.3The long processing times and high demand for testing kits and ancillary ingredients needed for sample preparation and processing represent serious bottlenecks for widespread testing. The whole process can provide results within 4 to 6 hours, although some centralised labs might require up to 48 hours from sample to answer. To respond to these challenges some companies are providing their kits and proprietary rapid point‐of‐care molecular diagnostic systems, mostly based on RT‐PCR, which include robotic automation and microfluidic handling of samples .As an alternative to PCR, the isothermal amplification of nucleic acids allows for extreme amplification of nucleic acids at constant temperatures. It bypasses the thermal cycling process in PCR, thereby shortening the test time and equipment cost significantly. Multiple isothermal amplification technologies have been developed, and some are already used for diagnosis of infectious diseases.Circumventing the need for thermal cycling means that the use of isothermal amplification decreases the complexity of the diagnostic device and reduces its cost. The amplified DNA can be detected by changes in turbidity, by addition of intercalating dyes or by a pH‐sensitive dye.2.4CRISPR‐based lateral‐flow assays are a new addition to the quickly evolving molecular diagnostics landscape. CRISPR is a powerful gene‐editing toolIn a race for CRISPR‐based diagnostics, Mammoth Biosciences and Sherlock Biosciences are using CRISPR as a molecular diagnostic tool, rather than as an editing tool, to create fast, cheap and accurate tests to detect infectious diseases, including COVID‐19. Mammoth uses CRISPR technology developed from Jennifer Doudna's laboratory and has created a DNA endonuclease‐targeted CRISPR trans reporter (DETECTR) platform to develop tests that can detect multiple coronavirus strains.The testing systems work by employing CRISPR nucleases, programmed to find a defined gene sequence. SHERLOCK uses the cleavage and degradation of neighbouring ssRNA by the proteins Cas13 to cleave and activate a fluorescent reporter, whereas DETECTR uses ssDNA and Cas12a. Upon finding the sequence of interest, the nuclease activates a cleavage capability, which generates a fluorescence signal after cleaving a reporter DNA strand present in the sample. The fluorescence signal confirms the sequence has been found.The workflow for both systems after RNA extraction requires pre‐amplification of DNA or RNA and ends with a lateral‐flow assay to reveal the results. As an example, Figure CRISPR diagnosis methods benefit from the high sensitivity of molecular diagnostics, the high selectivity of CRISPR and the fast speed and facile use of lateral‐flow assays. They are adaptable to new targets and offer a potentially rapid and specific read‐out. They can also be run several times on the same sample, decreasing the chance of false negatives. Further, the tests are being designed for the point‐of‐care setting, enabling cheap and widespread screening. Omitting the amplification step would be a significant improvement in this technology.2.5Sequencing of the viral genome helps identify and classify novel strains of coronavirus.Apart from surveillance testing, whole‐genome sequencing can provide high‐throughput diagnosis.33.1For scaling up the diagnosis of COVID‐19, rapid‐tests that rely on lateral‐flow assays are an attractive alternative to the qRT‐PCR test. These cellulose‐based devices are less reliable than RT‐PCR tests but can be performed at the point‐of‐care, or in community settings without the need for expensive equipment. Using antibody‐antigen recognition, rapid antigenic tests detect the presence of viral proteins, whereas serological tests target antibodies against SARS‐CoV‐2. It takes at least 5 days to acquire enough viral load to be detectable through antigenic tests and up to 7 days or longer to develop antibodies against the virus  and M (IgM). Their concentration increases with time until a plateau is reached for IgG, which can remain for long in the patient after recovery. Therefore, detection of IgG is indicative of past infection and potential immunity. Serology tests can be used to detect current and past exposure to SARS‐CoV‐2 and can be performed in batches in a laboratory or individually at point‐of‐care settings.Unlike antigenic testing, which can act as a complement to qRT‐PCR, serological testing plays a completely different role in the response to an outbreak and should not be used for clinical decision‐making. Quantifying the number of past infections helps assess the true extent of an outbreak and inform prevention and control strategies. Preliminary seroprevalence studies3.2Current rapid tests for influenza suffer from suboptimal sensitivity to rule out disease.There is a trade‐off between sensitivity and speed in rapid tests. Although point‐of‐care lateral‐flow immunoassays have been developed to diagnose COVID‐19 within 15 minutes  and performing pooled RT‐PCR tests may be a sensible way forward.5Table Isothermal amplification methods are a promising low‐cost alternative to replace traditional PCR devices. Bypassing the thermal cycle in the PCR process provides a faster amplification process, therefore, shorter sample‐to‐answer time. Using this technology, Abbott has developed ID NOW™ COVID‐19 assay that can provide a result within 5 min with a sensitivity of 0.125 copies/μL.In the long run, we envisage the development of mixed technologies, combining molecular diagnostics and lateral‐flow assays. The Accula SARS‐CoV‐2 test by Mesa Biotech uses RT‐PCR technology to amplify the RNA signal of SARS‐CoV‐2 followed by lateral‐flow assays to reveal the result, thereby circumventing the need for fluorescence probes and detectors. CRISPR‐based diagnosis represents a prime example where mixed technologies can lead, combining high specificity and sensitivity with efficient and low‐cost biosensors. Direct quantification of viral RNA with CRISPR, without the need for DNA amplification, would reduce the sample‐to‐answer time significantly. Repurposing Sanger sequencers and Next Generation Sequencers for COVID‐19 diagnostics, not only opens the door to tracking the virus evolution, but it can also be a tool for high‐throughput testing.R. In a population‐level study, even accurate tests can give high levels of false positives if the true prevalence is low. The choice of target populations and how tests are performed are important considerations. Mass screening representative samples of the population and contact tracing can guide public health authorities adapting their nonpharmaceutical interventions both in time and space, focusing the containment effort in affected communities and loosening lockdowns. It will also enable a quick assessment of the extent of the epidemic by identifying asymptomatic cases and determining what fraction of the population has ever been infected and might have acquired immunity to COVID‐19.The SARS‐CoV‐2 pandemic has caused an urgent need for rapid diagnostic testing and stirred up the biosensing sector. This quick development will continue, and some of the work in this review may change as more data on COVID‐19 becomes available and results are scrutinized. Accurate and widespread testing is mandatory to reduce the uncertainties associated with the number of infected cases, the case fatality rate and the effective reproduction number The author declares no conflict of interest.Ibon Santiago studied physics at the University of the Basque Country. He received an MSc from the Massachusetts Institute of Technology and a doctorate in physics from the University of Oxford, where he worked in DNA nanotechnology and active matter physics. He is currently Alexander von Humboldt Research Fellow at the Technical University of Munich. His research focuses on the physics of synthetic biological systems.


The lung achieves an efficient gas exchange between a complex non‐sterile atmosphere and the body via a delicate and extensive epithelial surface, with high efficiency because of elastic deformation allowing for an increase and decrease in volume during the process of breathing and because of an extensive vasculature which aids rapid gas diffusion. The lungs’ large surface area exposes the organ to a continual risk of damage from pathogens, toxins or irritants; however, lung damage can be rapidly healed via regenerative processes that restore its structure and function. In response to sustained and extensive damage, the lung is healed via a non‐regenerative process resulting in scar tissue which locally stiffens its structure, which over time leads to a serious loss of lung function and to increasing morbidities. This review discusses what is known about the factors which influence whether a lung is healed by regeneration or repair and what potential new therapeutic approaches may positively influence lung healing. This review discusses what is known about the detection, response and resolution of lung damage and what might influence whether a lung is healed by regeneration or repair. It also presents potential therapeutic approaches that may positively influence lung healing. The oxygenation of vertebrate tissues relies on lung structures that are both delicate and vulnerable to damage. Over a human lifespan, the lungs are exposed to hundreds of millions of litres of non‐sterile air whilst maintaining their function and integrity. Despite endemic respiratory infections, lung immunity is normally sufficient for resolution without lasting structural damage. Such favorable outcomes have been significantly enhanced through the use of therapeutic antibacterial treatments. Nevertheless, sustained or more extensive lung infections can occur resulting in the accumulation of fibrotic damage which chronically affects the lungs’ flexibility and oxygen permeability.This review seeks to compare physiological lung regeneration following damage with repairs which result in scar tissue disrupting normal lung structure. We analyse the contribution of the immune response to these outcomes. Undoubtedly, the level of inflammation within the lung in the aftermath of tissue injury is one of the key factors that regulates physiological versus fibrotic repair. We discuss the latest research developments in the field, ultimately trying to understand whether we can harness this knowledge to modulate the inflammatory response in damaged lungs to enhance the lungs’ regenerative potential.The high vulnerability of the lungs to damage is associated with its structure. Firstly, the lung has a very low density of cells relative to its volume. Secondly, the functional efficiency of the lung is dependent on the organisation and composition of a range of cell types whose structural characteristics are responsible for a combination of elasticity and permeability. The most vulnerable lung cells to damage are those located at the mucosal surface. Damage to the epithelial cells stimulates rapid proliferation, differentiation and recruitment of replacement cells and can result in the regeneration of the barrier function of the tissue. However, alteration of the cellular organisation caused by repair processes that involve scarring necessarily alters critical structural characteristics, leading to poorer lung function. Factors such as the amount and cell types damaged, the disruption of barrier function and the strength and duration of the local immune response, can determine whether a damaged lung regenerates, is repaired or fails to repair leading to chronic lung disease.The disruption of tissue homeostasis caused by damage rapidly changes the local microenvironment adjacent to the damaged lung. The wound environment becomes positive for molecules derived from pathogens which contaminate it and from the intracellular environment of dying cells. The survival advantage given by the rapid detection of tissue damage has driven the evolution of cellular receptors that recognise conserved structural elements frequently found in pathogens and on intracellular cell components that are only released following damage. Such receptors are termed pattern recognition receptors (PRR) and include the Toll‐like receptors and the retinoic acid‐inducible gene I (RIG‐1)‐like receptors. Molecules derived from pathogens and recognised by specific PRR are called pathogen‐associated molecular patterns (PAMPs), whilst ligands that derived from damaged host cells are known as danger‐associated molecular patterns (DAMPs).Early after injury, damaged cells release DAMPs such as IL (Interleukin)‐1α  and the NLRP3 component of the inflammasome. Increased inflammasome activity drives the activation of pro‐IL‐1 β production, and release of this and other cytokines results in a strong pro‐inflammatory response. Stromal cells respond by secretion of additional pro‐inflammatory cytokines such as IL‐6, the level of which is critical in driving fibrosis  and are specifically activated by ligands associated with encountered pathogens or released from damaged tissue cells that contain conserved structural elements. The importance of the rapidity of this response mediated first via recruitment of granulocytes from the bloodstream is indicated by neutropenic cancer patients experiencing a much higher relative risk of mortality.If the host has pre‐existing humoral immunity to the invading pathogens, interactions occur with the innate immune response. Low‐affinity type I Fcγ receptors (FcγR), expressed heterogeneously on leukocytes,In the absence of pre‐existing immunity, the activation of neutrophils and other leukocytes such as tissue‐resident immune cells such as alveolar macrophages,In particular, secretion of IL‐12 and IL‐23 by local DC influences the differentiation T helper (Th)‐1 cells and Th17 cells, respectively.In parallel with the local immune response, tissue cells are stimulated to secrete extracellular matrix components and the proteases needed to remodel it. Cells proliferate and/or differentiate, and finally, excess cells undergo apoptosis in response to a reduction in the local levels of growth factors,In the lungs, the epithelial lining of the respiratory tract is highly susceptible to damage from airborne infection, irritants or airborne toxins. These linings readily regenerate following superficial damage which has not destroyed underlying tissue structure and extracellular matrix. In the lung, acute damage to the epithelium can stimulate an effective regenerative response driven by proliferative responses from healthy adjacent epithelium.The importance that tissue remodelling plays during an effective regenerative process is shown by a study by Schiller and colleagues.During effective lung regeneration, the basement membrane underlying the epithelial and endothelial cell layers is thought to be critical in supporting stem cell migration into the damaged area through its provision of a scaffoldIn vitro studies have shown that decorin mRNA can be increased by the corticosteroid, dexamethasone (Dex), whilst biglycan mRNA is increased by all trans‐retinoic acid treatment (ATRA).At day 3, which corresponds to the peak of the inflammatory response following bleomycin treatment, there is a significant upregulation of secreted neutrophil elastase inhibitor, α2‐macroglobulin and a range of serine protease inhibitors (serpins),Under conditions of chronic inflammation, the continued recruitment and activation and degranulation of neutrophils lead to tissue damage mediated by proteases including elastase, which digests extracellular matrix proteins and can disrupt structure provided in the lung by the basement membrane that underlies the alveolar epithelium. When the structural integrity of the lung is damaged, repair processes dominate over regeneration. This is illustrated in an elegant study using the elastase chronic lung damage model where the amount of damage to the lung was titrated over 4 sequential weekly low doses of pancreatic porcine elastase (PPE).Recent comparisons of the similarities and differences of the damaging effects of silica, bleomycin and paraquat in an animal model suggest that these agents damage the lung in different and characteristic ways.The consequences of prolonged or repeated periods of infection, irritants or toxins can induce a state of chronic inflammation, a tissue environment in which repair processes that replace the normal tissue architecture with fibrotic tissue are favored over tissue regeneration. If multiple areas of the lung are affected in this way, then lung function is progressively and irreversibly reduced.et al. proposed that small airways are susceptible to particle‐driven damage which precedes the collapse of terminal bronchioles, leading to life‐threatening increases in airway resistance, characteristic of the pathological progression of chronic obstructive pulmonary disease (COPD).The lung’s structural characteristics result in dynamic and distinct environmental and mechanical properties which vary along the ventilatory tree from trachea to terminal alveoli. Insights into the differential susceptibility of lung structures have been gained via the integration of physiological measurements of intra‐airway pressureIn contrast, lung diseases such as pulmonary fibrosis do not seem to be predominantly driven by particle damage and subsequent chronic inflammation and are insensitive to anti‐inflammatory treatment.Current and proposed therapeutic approaches to halt chronic lung damage involve reducing lung inflammation, with the most common treatment regimens seeking a broad abatement of pro‐inflammatory signalling through the use of inhaled corticosteroids. However, as discussed above, current anti‐inflammatory approaches are not effective in treating IPF. An illustration on how corticosteroid treatment might have untended negative effects on damaged lung is provided in a recent study assessing the ability of Dex treatment to improve outcome following bleomycin‐induced lung damage. This study reported that Dex‐treated mice showed a reduction in tumor necrosis factor (TNF)‐α concentration in lavage fluid; however, there was no significant reduction in neutrophil numbers in Dex‐treated mice. Additionally, cultures of primary alveolar epithelial cells treated with Dex showed a delayed and dose‐dependent lower repair rate than saline‐control‐treated cultures.There are important clinical issues with the efficacy of these treatment regimens in humans including the development of steroid‐resistant inflammationThe identification of DAMP and PAMP as molecules critical to the initiation and maintaining of inflammation has prompted pre‐clinical studies to assess the effectiveness of DAMP/PAMP blockade in the resolving inflammation. Whilst not technically a DAMP, IL‐1β is an important part of the signalling amplification that follows DAMP or PAMP activation of the inflammasome complex. There are three types of reagents targeting IL‐1 that have been evaluated for anti‐inflammatory activity in the context of lung diseases: anakinra is an IL‐1 receptor antagonist,The cytokine IL‐5 is a current anti‐inflammatory therapeutic target and has been detected in bronchial lung biopsies of asthmaticsOther reagents being assessed for the treatment of lung disease include tocilizumab, a humanised monoclonal antibody which blocks the activity of the interleukin‐6 receptor (IL‐6R). This reagent has been trialled in the context of the interstitial lung disease (ILD) that is associated with systemic sclerosis in patients diagnosed for less than 2 years.Numerous animal studies have demonstrated the role that the IL‐17 family of cytokines play in inflammatory lung disease and that blocking IL‐17aOn balance, the failure to demonstrate improved outcomes following treatments with biologics directed against a range of inflammatory cytokines is discouraging but given the efficacy of such approaches in treating other inflammatory conditions, then additional dosing approaches or perhaps multi‐target biologics+ interstitial myofibroblasts that are derived from a sub‐population of platelet‐derived growth factor‐alpha+ fibroblasts that respond to peroxisome proliferator‐activated receptor‐γ (PPAR‐γ).As described above, the lung has the capacity to regenerate, especially the lung epithelium, a process that is dependent on the survival of suitable progenitor cells located within a viable distance of the damage site. Recent fate lineage tracking of alveolar progenitor cells in mice describes an ongoing but infrequent generation of new alveolar units, with ATII cells acting as progenitors for ATI cellsin vitro studies have demonstrated that exosomes, which are small membrane vesicles containing mixed concentrations of cytoplasmic molecules, are released from cultured adipose‐derived MSC. These exosomes both contain and express alpha‐1‐anti‐trypsin on their surface,The demonstration of the pluripotency of mesenchymal stem cells (MSC) has naturally suggested that they might play apart in regenerative processes. The adoptive transplantation of MSC has been shown in multiple studies to have pro‐regenerative and anti‐inflammatory effects, often when they accumulate in lung tissues. For example, adoptively transferred MSC have shown positive benefits in the context of bleomycin‐induced lung injury in mice,et al.Other studies have looked at the effectiveness of treating lung damage with all trans‐retinoic acid (ATRA) given that it has a structural relationship to vitamin A and has been shown to be involved in lung development.2 (PGE2) induces a switch from the production of the pro‐inflammatory leukotriene beta‐4 (LTB4) to the molecule lipoxin which acts to reduce further neutrophil recruitment ‐1 and 2 enzymes are involved in the biosynthesis of prostaglandins and are the targets of the non‐steroidal anti‐inflammatory inhibitors, which include aspirin. Activation of neutrophils by the prostaglandin‐Et Figure . The proThese pre‐clinical studies give hope that even in badly damaged lungs, function can be partially restored, whilst it is clear that a deeper understanding of the mechanisms underlying lung restoration is still to be achieved.The challenge to prospectively assist in the recovery from lung damage and improve clinical outcomes lies in the developing of treatments that enhance regenerative over repair processes. As discussed above, the management of the inflammatory response appears key to these improvements. The application of anti‐cytokine agents now available in the clinic such as anti‐IL‐1 and anti‐IL‐6 might be considered then to modulate acute inflammatory responses, with potential benefits balanced against other clinical risk factors. For example, the enhanced risk of infection might be reduced by co‐treating with anti‐pathogen medications. Further understanding the scope and power of endogenous anti‐inflammatory molecules, such as resolvin‐like molecules, whose efficacy might be affected by the diet, has the potential to positively affect lung healing potential, at a population level.The authors declare no conflict of interest.