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• Published: 24 April 2024

A high-density and high-confinement tokamak plasma regime for fusion energy

• S. Ding   ORCID: orcid.org/0000-0002-1930-0439 1 ,
• A. M. Garofalo 1 ,
• H. Q. Wang   ORCID: orcid.org/0000-0003-1920-2799 1 ,
• D. B. Weisberg 1 ,
• Z. Y. Li   ORCID: orcid.org/0000-0003-3932-9244 1 ,
• X. Jian 1 ,
• D. Eldon 1 ,
• B. S. Victor 2 ,
• A. Marinoni   ORCID: orcid.org/0000-0003-1004-5782 3 ,
• Q. M. Hu   ORCID: orcid.org/0000-0002-8877-4988 4 ,
• I. S. Carvalho   ORCID: orcid.org/0000-0002-2458-8377 1 ,
• T. Odstrčil 1 ,
• L. Wang 5 ,
• A. W. Hyatt 1 ,
• T. H. Osborne 1 ,
• X. Z. Gong 5 ,
• J. P. Qian 5 ,
• J. Huang 5 ,
• J. McClenaghan 1 ,
• C. T. Holcomb 2 &
• J. M. Hanson   ORCID: orcid.org/0000-0003-2432-4870 6  

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• Magnetically confined plasmas
• Nuclear fusion and fission

The tokamak approach, utilizing a toroidal magnetic field configuration to confine a hot plasma, is one of the most promising designs for developing reactors that can exploit nuclear fusion to generate electrical energy 1 , 2 . To reach the goal of an economical reactor, most tokamak reactor designs 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 simultaneously require reaching a plasma line-averaged density above an empirical limit—the so-called Greenwald density 11 —and attaining an energy confinement quality better than the standard high-confinement mode 12 , 13 . However, such an operating regime has never been verified in experiments. In addition, a long-standing challenge in the high-confinement mode has been the compatibility between a high-performance core and avoiding large, transient edge perturbations that can cause very high heat loads on the plasma-facing-components in tokamaks. Here we report the demonstration of stable tokamak plasmas with a line-averaged density approximately 20% above the Greenwald density and an energy confinement quality of approximately 50% better than the standard high-confinement mode, which was realized by taking advantage of the enhanced suppression of turbulent transport granted by high density-gradients in the high-poloidal-beta scenario 14 , 15 . Furthermore, our experimental results show an integration of very low edge transient perturbations with the high normalized density and confinement core. The operating regime we report supports some critical requirements in many fusion reactor designs all over the world and opens a potential avenue to an operating point for producing economically attractive fusion energy.

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Fusion energy is the ultimate energy source for humanity 16 . A promising approach is a steady-state fusion reactor using magnetic confinement in the tokamak configuration 17 , 18 . With a deeper understanding of tokamak plasma physics and the development of reactor-relevant technologies, many fusion reactor designs have been proposed 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 . When the ion temperature is above 13 keV (1.5 × 10 8  K) in D–T fusion reactions, the thermonuclear power density 19 P fus  =  n fuel 2 ⟨ σv ⟩ E /4 is proportional to the fuel density ( n fuel ) squared, as the change of normalized reaction rate ⟨ σv ⟩ with temperature is relatively small. Here, E is the fusion energy released per reaction. Detailed definitions of all variables mentioned in this paper can be found in Extended Data Table 1 . Therefore, to achieve attractive fusion goals, most of the recent fusion pilot plant (FPP) designs require very high plasma densities, higher than the empirical edge density limit known as the Greenwald density 11 ( n Gr ), in tokamak high-confinement mode (H-mode) plasmas 13 . The energy confinement quality, represented by the H-factor 20 (for example, H 98y2 ), is believed to be the highest leverage parameter for fusion capital cost 8 . H 98y2 is usually required to exceed the standard H-mode level ( H 98y2  = 1.0) for good fusion economy. FPP designs 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 simultaneously require 1 ≤ Greenwald fraction ( f Gr ) ≤ 1.3 and 1 ≤  H 98y2  ≤ 1.65. However, such a tokamak operating regime is an uncharted area that has never been verified in experiments.

The empirical n Gr is a density limit for the pedestal density in an H-mode plasma 21 , 22 . The pedestal is a narrow region of plasma at the edge with suppressed turbulent transport and a steep pressure gradient. When approaching n Gr at the pedestal, various unfavourable phenomena can be observed in experiments. These cause a strong decrease of the confinement quality or even a sudden, complete loss of plasma energy (disruption) 22 . A peaked core density profile is, therefore, required to achieve a line-averaged density above the pedestal density limit. Possible approaches include relying on the natural peaking at low collisionality 23 and the potential inward particle pinch 24 . The previous DIII-D experiment 24 can achieve a transient f Gr of about 1.4 with D 2 gas puffing. A large pinch velocity has been measured. H 98y2 in this case is around 1. ASDEX Upgrade experiments took a different approach by using pellet injection to improve the core fuelling. The experimental results show a transient f Gr  ≈ 1.5 with pellet injection 25 , 26 . However, the H 98y2 values in those discharges were less than 1. More examples with H 98y2  < 1 at high density are well documented 22 . As no tokamak experiment has yet attained a sustained f Gr above 1 and H 98y2 well above 1 (for example, 1.5) at the same time, experimentally verifying the desired operating regime in FPP designs is a great challenge for the magnetic confinement fusion community.

Another challenge with H-mode reactor plasmas is the very high transient heat load produced by quasi-periodic edge magnetohydrodynamic (MHD) instabilities known as type-I edge-localized-modes (ELMs). Without control, ELMs in a reactor can severely damage plasma-facing-components, for example, the first wall 27 , 28 . ELM control is an active research area and various approaches have been proposed 29 , 30 , 31 , 32 , 33 . However, compatibility among small/no ELM solutions, high density (above n Gr ) and high confinement quality ( H 98y2 well above 1, for example, 1.5) has not been demonstrated in experiments.

We report a new experimental approach for achieving a line-averaged density above n Gr . It exploits an operating regime recently established in the DIII-D tokamak that allows simultaneous f Gr  > 1.0, H 98y2  ≈ 1.5 and small ELMs and could support many existing designs for future reactors 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 . The approach elevates the plasma density in the core while keeping the pedestal fraction of the Greenwald density at moderate levels (for example, f Gr,ped  ≈ 0.7), thus not violating the empirical density limit. It does so by exploiting self-organized internal transport barriers (ITBs) at large minor radius in the high poloidal-beta ( β P ) scenario 15 , 34 , 35 , 36 . More information about the high- β P research can be found in Methods . In experiments, the on-axis fraction of the Greenwald density ( f Gr,0 ) can reach up to 1.7, resulting in a line-averaged f Gr of 1.3. ITBs in the density and temperature profiles also greatly improve the energy confinement quality ( H 98y2 up to 1.8), compared to the standard H mode ( H 98y2  = 1) at the same engineering and operating parameters.

Figure 1 shows a plot of the DIII-D database and illustrates the progress made in extending the plasma operating space towards high f Gr and high H 98y2 . The 2019 high- β P experiments with impurity injection 15 have simultaneously achieved f Gr  > 1.0 and H 98y2  > 1.0. However, in these experiments, too much impurity injection also increases the radiative energy loss in the plasma core, limiting H 98y2 at high density. Of the violet diamonds in Fig. 1 , some have H 98y2  ≤ 1.2 when f Gr  ≥ 1.15. However, these results are not good enough for FPP designs. A major improvement in the 2022 DIII-D high- β P experiment used additional D 2 gas puffing (Fig. 2 ) instead of impurity injection. This approach effectively reduces the core radiation and improves H 98y2 , as shown in Fig. 1 (blue squares). Thus, this paper reports a clear experimental demonstration of an accessible operating point in an existing tokamak that can meet a few of the FPP requirements, including simultaneous f Gr  > 1 and H 98y2  ≈ 1.5. For comparison, other scenarios presented run on DIII-D have not achieved such simultaneous normalized performance (yellow circles).

More than 3,600 discharges are included. Violet diamonds show high- β P experiments performed in 2019 with impurity injection. Blue squares are the new high- β P experiments performed in 2022 without impurity injection. Yellow circles represent all other experiments performed in 2019–2022. The area shaded in orange indicates the parameter space for attractive FPP designs. Vertical and horizontal dashed lines show f Gr  = 1.0 and H 98y2  = 1.0, respectively.

a , f Gr in blue and H 98y2 in green. b , β N in blue, β P in green and q 95 in violet. c , D 2 gas puffing in feedback control in black and dedicated feedforward D 2 gas puffing in vermillion. d , Peak pedestal electron density gradient in blue and pedestal total pressure in vermillion. e , Separatrix electron density in green and ratio between pedestal electron density and separatrix electron density in violet. f – i , Profiles of electron temperature ( f ), ion temperature ( g ), electron density ( h ) and carbon density ( i ) at the time slices shown in the vertical dashed lines in a . Dots with error bars are measurements. j – l , D α data for the three periods shown in the shaded area in d . a.u., arbitrary units. m – o , Total pressure profiles at the time slices of the vermillion dots in d .

Figure 2 shows detailed data from an example discharge (190904) in 2022. The striking feature in this discharge is the dynamic synergy between energy confinement quality and plasma density. That is, H 98y2 increased along with f Gr (Fig. 2a ) until the ramping down of the heating power (Extended Data Fig. 1e ). This is opposite to the common observation of reduced energy confinement quality in higher density H modes 22 , especially for experiments close to the Greenwald density. The plasma was maintained at f Gr  > 1.0 and H 98y2  > 1.0 for about 2.2 s, which was 2.2 times the current diffusion time ( τ R ) or 24 times the energy confinement time ( τ E ). Thus, the high normalized density and confinement phase was not transient, which is imperative for application in future long-pulse FPPs. A normalized plasma pressure β N  ≈ 3.5 and β P  ≈ 2.9 was achieved at safety factor q 95  ≈ 8.5 (Fig. 2b ) with plasma current I p  = 0.73 MA and toroidal magnetic field B T  = 1.89 T, and with mixed co- and counter- I p neutral beam injection (NBI). Note that n Gr  = 6.7 × 10 19  m −3 in this discharge, close to the Greenwald density of the ITER 9 MA steady-state scenario at 7.2 × 10 19  m −3 . The dedicated D 2 gas puffing time trace is shown in vermillion in Fig. 2c . This approach ensures that there is a sufficient source of particles in the plasma, and it pushes the plasma density to a higher level, regardless of the change in the feedback gas (black line in Fig. 2c ).

Profiles of the temperature and density for electrons, deuterium (main ion) and carbon (main impurity) are shown in Fig. 2f–i and Extended Data Fig. 2a . The evolution of the on-axis densities for electrons, deuterium and carbon is displayed in Extended Data Fig. 1c . One can see that ITBs developed in all density channels. The increased deuterium density in this experiment suggests the promising application of this scenario in future FPPs, as it can attain a higher fuel density to give a higher fusion power. A related piece of experimental evidence is shown in Extended Data Fig. 1d . It is clear that with increased plasma density and energy confinement, the neutron rate, an indicator of fusion performance, increased substantially (67% higher, from 0.6 × 10 15 to 1.0 × 10 15  s −1 ) from 2 to 4.8 s, whereas the injected power (blue line in Extended Data Fig. 1e ) was almost constant. Moreover, a very mild increase of the radiated power was observed in the very-high-density phase of the experiment (Extended Data Fig. 1e ). The core radiated power as a fraction of the injected power increased from 10% to 20% as f Gr increased from 0.7 to 1.1. The edge radiation remained about 25% of the injected power. Note that for either Bremsstrahlung radiation or impurity line emission, the radiated power was roughly proportional to the electron density squared. Therefore, some increase in the radiated power was expected even with the same impurity level, when the plasma density was increased significantly. Regarding the impurity behaviour, one can see a well-developed ITB at large radius in the carbon density profiles (Fig. 2i ). Despite the ITB at large radius, the carbon density inside the ITB did not have a significant central peak, which would usually cause a large amount of core radiation and a reduction of core performance. The ratio between carbon density and electron density stayed around 4–5% during the evolution (Extended Data Fig. 2b ). This is consistent with the well-controlled radiated power in the phase with f Gr  > 1.0.

The evolution of the safety factor profile ( q -profile) is shown in Extended Data Fig. 2c . The figure shows the self-organized q -profile evolution, which reflects the change of the local bootstrap current density associated with the development of a large-radius ITB. The local minimum q ( q min ) in the outer half of the plasma was at ρ  ≈ 0.6 for around 2 τ R . q min in this discharge stayed above 2.

When a density ITB built up over time and was sustained, the total pedestal pressure at ρ  = 0.88 did not change significantly (Fig. 2d ). However, other pedestal parameters and the ELM behaviour changed. At f Gr  < 0.8, typical standard H-mode pressure profiles and typical large type-I ELMs were observed (Fig. 2j,m ). At 0.8 ≤  f Gr  < 1.0, pressure profiles with an ITB and compound ELMs emerged (Fig. 2k,n ). Finally, pressure profiles with a large ITB and small ELMs dominated the f Gr  ≥ 1.0 phase (Fig. 2l,o ). During the evolution, a decreased peak pedestal electron density ( n e,ped ) gradient, increased separatrix electron density ( n e,sep ) and decreased ratio between n e,ped and n e,sep were observed, as shown in Fig. 2d,e . These parameter evolutions are consistent with the favourable conditions needed to access the small-ELM regime discussed in the literature 29 . A more detailed modelling analysis of the pedestal for different ELM behaviours will be discussed later in this paper.

Although addressing the transient heat load is crucial, mitigating the stationary heat load is equally important for an FPP. Divertor detachment is widely considered to be a necessary solution for realizing an acceptable stationary heat load in the operation of future FPPs. Even without detachment-oriented impurity seeding, Extended Data Fig. 3 shows that the electron temperature at the divertor plates ( T e,div ) clearly reduced from over 35 eV (before 1.8 s) to 20–25 eV (1.8–2.8 s) and finally to 10–15 eV (after 2.8 s) in the f Gr  > 1.0 and H 98y2  ≈ 1.5 phase, and there were small ELMs. The lowest T e,div phase is consistent with the existence of an ITB at large radius. Although T e,div  ≤ 15 eV is not yet considered as divertor detachment (usually T e,div  < 10 eV), it already suggests that there would be mitigation of tungsten erosion under the experimental stationary heat load, if a tungsten wall had been used. Note that although the integration of full divertor detachment and high-confinement core has been achieved in previous DIII-D high- β P experiments and reported 15 , 37 , the experimental approach and the operating parameter space were both different. The previous results used impurity seeding and f Gr  ≈ 0.9, which are not sufficient for FPP designs.

Therefore, the analysed typical DIII-D high-β P discharge has demonstrated a sustained, accessible operating point in a present tokamak that integrates high normalized density and confinement quality, small ELMs and reduced divertor electron temperature, thus addressing the key requirements of FPP designs for simultaneous high-performance core and excellent core-edge integration.

To understand the physics that enables high confinement quality at high normalized density, we performed a gyro-fluid transport analysis using the TGLF code 38 on the experimental data from the discharge shown in Fig. 2 . Figure 3a,b shows the dependence of the normalized electron turbulent heat flux Q e / Q GB (where  Q GB is the Gryo-Bohm heat flux) on the fractional contribution of the density gradient to the pressure gradient ( F p  =  T ∇ n / ∇ p ) at mid-minor radius in the plasma. The gyro-fluid modelling indicates that when using either numerical approach to vary F p (constant ∇ T or constant ∇ p ), the decreasing trend of Q e for increasing F p is robust. A similar result was obtained for the ion energy transport. These results reveal an important feature in the high- β P scenario, namely that anomalous turbulent transport, which leads to poor global confinement, can be reduced with a high density gradient, that is, a high density in the core with the pedestal density maintained below n Gr . This is consistent with the experimental observation of synergy between high confinement quality and high density. If F p were increased by 30%, the normalized Q e would decrease by a factor of 2 compared with the prediction at the experimental value, when the normalized pressure gradient α MHD (approximately − q 2 / B T,unit 2 R d p /d r ) was moderate (1.13), as shown in Fig. 3a . However, the reduction of the transport can be 2–3 orders of magnitude stronger when α MHD is high (2.75) in the experimental equilibrium (Fig. 3b ). Note that this finding is also consistent with the previous nonlinear gyro-kinetic theoretical modelling 39 , which found an extreme reduction in the transport coefficient when high α MHD was combined with moderate density gradients. The underlying physics includes 1) the low drive of the ion-temperature-gradient turbulence at high density gradient (that is, there is a low ratio between the density gradient scale length and the ion temperature scale length ( η i )), and 2) less effective coupling between trapped electrons and the trapped-electron-mode turbulence owing to the much narrower turbulence eigenfunction at high α MHD .

a , Moderate α MHD case from the high- β P discharge in Fig. 2 . F p scan with the constant ∇ p approach in blue and with the constant ∇ T approach in vermillion. The experimental (Exp.) value of F p is indicated by the black arrow. b , High α MHD case from the high- β P discharge in Fig. 2 . Same colour coding as in a . c , d , Temperature ( c ) and density ( d ) profiles for the low- q 95 H-mode case analysed in e and f . Dashed lines show the radial location for transport analysis. e , f , Two-dimensional scans of normalized electron turbulent heat flux on F p and local q based on the low- q 95 H-mode data shown in c and d . Full experimental β e ( e ) and half experimental β e ( f ). The experimental data point from the low- q 95 discharge is indicated by a blue star in e .

We also applied the same gyro-fluid transport analysis to a standard H-mode discharge to reveal the requirement for realizing the favourable conditions for low transport at high density. A low- q 95 standard H-mode discharge (DIII-D 187019) with strong D 2 gas puffing and high density was investigated. Compared with the high- β P discharge discussed above, this discharge had the same heating power (9 MW), comparable line-averaged density (5.0–6.5 × 10 19  m −3 ), slightly lower β N (approximately 2.5), but much lower q 95 (4 versus 8.5). This was because of a much higher I p (1.3 versus 0.73 MA). Typical standard H-mode profiles are shown in Fig. 3c,d , which are different from the ITB profiles in Fig. 2 . Figure 3e presents the transport analysis of a two-dimensional scan on F p and local q at ρ  = 0.65. The modelling uses the experimental β e value. As illustrated by the horizontal dashed lines, the figure can be roughly divided into three regimes. At low local q , such as for the standard H-mode experimental data point, the modelling predicts high turbulent transport at high F p . This is consistent with the experimental observation of decreased H 98y2 at high density in this discharge. At medium q , transport is predicted to be almost independent of F p . Finally, low transport at high F p can be found in the high- q regime (top right corner of this figure highlighted by the blue dashed line). This example suggests that a minimum of the local q  ≈ 4.4 is required to access this regime. Note that the analysed high- β P case has local q  ≈ 5.1. However, high local q alone is insufficient to access this regime. Figure 3f indicates the importance of sufficient β e , or the plasma pressure ( β ). Note that β changes accordingly in the modelling when scanning β e . The range of the two-dimensional scan is the same. However, this scan uses half of the experimental β e in the modelling. As one can see, the results are significantly different. For most of the q values in the scan, high turbulent transport at high F p is predicted. The favourable low transport at high F p may still exist but probably requires very high local q , which is less realistic in present tokamak experiments or future machine designs.

In summary, the transport analysis suggests that the standard H-mode could access the favourable low-transport regime at high density, with the following necessary conditions: high local q and high plasma pressure β , which are two key components in the expression of α MHD . Thus, sufficient α MHD is essential for realizing the favourable operating regime. As summarized in the literature 15 , 37 , 40 , α-stabilization is considered as the primary turbulence suppression physics in the high- β P scenario, as it provides a reactor-relevant rotation-independent mechanism for high confinement 40 . On the other hand, given that β P   ∝   β N q 95 , high q 95 and high β N lead to high β P . Therefore, the high- β P scenario is naturally an excellent candidate for pursing this goal.

We performed a pedestal analysis to evaluate the pedestal stability and understand the evolution of the ELM behaviour in the high- β P discharge described in Fig. 2 . The ELITE calculations 41 shown in Fig. 4a predict the stability boundary for peeling–ballooning modes in the pedestal, for each of the three ELM states. In the type-I ELM state, the pedestal lies near the unstable ballooning region. Evolving to the small-ELM state, the experimental point moves along the ballooning boundary towards a lower pedestal pressure gradient and lower pedestal current density. Moving further away from the peeling boundary is consistent with the observation of no giant ELMs in the later phase. Modelling with BOUT++ (refs. 42 , 43 , 44 ) provides details on the instability growth rate in Fig. 4b . The dominant low- n peeling–ballooning mode was identified at n  ≈ 10, which agrees with the ELITE result. The predicted low- n growth rate is smallest for small ELMs. BOUT++ modelling also resolves high- n resistive ballooning modes near the separatrix, when considering the plasma resistivity. It is clear that the high- n separatrix modes are dominant in the small-ELM case in contrast to other results in Fig. 4b . The modelling suggests that the high- n separatrix modes played an essential role in the observation of small ELMs in high- β P plasmas.

a , b , Results for the type-I ELM in blue, the compound ELM in green and the small ELM in violet. a , Pedestal stability versus normalized pedestal current density ( y axis) and normalized pressure gradient at the pedestal peak gradient location ( x axis). j max , j sep and ⟨ j ⟩ are the maximum pedestal current density, the current density at the separatrix and the average current density in the pedestal region, respectively. Stability boundaries are shown as solid lines. Experimental points are indicated as open squares with error bars. b , Linear mode growth rate (normalized by Alfvén frequency, ω A ) at different toroidal mode numbers.

In this paper, we have extended the operating space of a tokamak plasma towards a regime with simultaneous f Gr up to 1.25 and H 98y2  ≈ 1.3–1.8, using the high- β P scenario in DIII-D. The achievement of entering this previously uncharted regime provides essential support to many attractive FPP designs all over the world. The increased deuterium density and neutron rate in the experiment confirm the promising application of this scenario for higher fusion performance in future FPPs. Unlike many previous high-density H-mode experiments, the high- β P scenario uniquely features a synergy between high confinement quality and high density, especially around the Greenwald value. We have also elucidated the important role of α-stabilization in this achievement, showing that the favourable regime of low turbulent transport at high density is predicted and achieved only at relatively high local q and high β , namely for sufficient α MHD at high β P . This successful experiment not only addresses a few of the key requirements on FPP core plasma parameters but also suggests a potential solution for core-edge integration by demonstrating sustained small ELMs together with f Gr  > 1.0 and H 98y2  > 1.0. Realizing the small-ELM regime is understood as a combination of the reduced growth rate of low- n modes and the predominance of the high- n resistive ballooning mode near the separatrix because of the decreased peak density gradient in the pedestal, increased separatrix density and high β P . During the natural small-ELM phase with a high normalized density and confinement, the plasma is close to divertor detachment, which is believed to be the most promising solution for achieving steady-state plasma–wall-interactions in FPPs 37 , 45 . The natural proximity of detachment conditions shows the potential of a fully integrated scenario with high-performance core and cool edge. As the divertor detachment was not optimized in the discussed experiment, doing so will be important work for future experiments. Note that the compatibility of the high- β P scenario with full divertor detachment has been demonstrated 37 . So far, neither a significant central peak in the density profile of the impurity (carbon) nor a significant increase in the core radiated power has been observed when the density is above the Greenwald value. Dedicated impurity transport experiments and modelling work are also under consideration for this operating regime. Fast-particle confinement is important for future FPPs. Experiments on the high- β P scenario in DIII-D usually exhibit classical fast-ion transport. More discussion of previous results is presented in ‘DIII-D high- β P experiments’ ( Methods ).

We fully appreciate that further work is needed to address other critical issues related to FPP compatibility, for example, operating with a metal wall and helium exhaust. On DIII-D, limited experiments with high- β P plasmas operating with a divertor strike point on a (temporary) ring of tungsten tiles have shown promising results, with no significant degradation of core performance. However, to fully address the compatibility with a metal wall, we are collaborating closely with the Experimental Advanced Superconducting Tokamak (EAST) and Korea Superconducting Tokamak Advanced Research programme in the development of high- β P scenarios so that we can exploit their metal wall and long-pulse operation capabilities. Long-pulse operation (over 10 s) will further address the alignment for steady-state q -profiles and pressure profiles with ITB in the high- β P scenario. With regard to the helium exhaust, several review papers give favourable conclusions for high- β P plasmas with ITBs in JT-60U 46 , 47 . The results for JT-60U high- β P ITB plasmas show that the helium density in the core was controlled well and that no helium accumulation was observed, even with helium NBI for the core helium source. Moreover, the results also emphasize the importance of helium exhaust techniques, such as pumping, for controlling the helium content in the core.

Furthermore, there has been recent activity on extending the high- β P scenario towards true long-pulse operation, including modelling work for EAST 48 , ITER 49 , 50 and FPPs under design 10 . Depending on the design philosophy of each group, the high- β P scenario can be applied in a wide range of FPP designs, from large conventional tokamaks 14 to relatively small and compact devices 9 , 10 . One example from CAT-DEMO (Case D) 9 shows a possible design point of an FPP using the high- β P scenario: R  = 4 m, R / a  = 3.1, B T  = 7 T, I p  = 8.1 MA, q 95  = 6.5, f Gr  = 1.3, f Gr,ped  = 1.0, β N  = 3.6, H 98y2  = 1.51, fusion gain Q  = 17.3 and output electric power 200 MWe. The experimental achievement and the increased understanding reported in this paper may open a potential avenue to an operating point for producing economically attractive fusion energy.

DIII-D tokamak

The DIII-D National Fusion Facility 51 is a tokamak research device operated by General Atomic in San Diego, California, for the US Department of Energy. DIII-D is the largest magnetic fusion research facility in the USA. The DIII-D programme is focused on establishing the scientific basis for the optimization of the tokamak approach to fusion energy production, in part through the development of advanced steady-state operating scenarios. The major and minor radii of DIII-D are 1.66 and 0.67 m, respectively. The toroidal field is up to 2.2 T at the magnetic axis, and the plasma current is up to 2 MA. DIII-D has four high-power NBI systems with a total power of up to 20 MW. Unique features of the DIII-D NBI systems include: (1) two horizontally rotatable beamlines, providing a capability for switching the off-magnetic axis neutral beam current drive from the co plasma-current direction to the counter plasma-current direction and (2) two vertically movable beamlines that enable the selection of on- or off-magnetic axis plasma heating and current drive in the experiment. DIII-D has six operational gyrotrons for heating the electron cyclotron and driving the current in the plasma. Each gyrotron is designed for 1 MW continuous-wave operation for several seconds at a central frequency of 110 GHz. Steerable antennas offer flexible heating and current drive methods in the plasma, including mid-plane launchers and top launchers. DIII-D is also developing a helicon system and a lower-hybrid wave system for additional radio-frequency heating and current drive capabilities. The extensive diagnostic set and the sophisticated plasma control system support various plasma experiments on DIII-D.

DIII-D high- β P experiments

Many international tokamaks have investigated high- β P scenarios 34 , 35 , 52 , 53 , 54 , 55 , 56 , 57 ever since these scenarios were first proposed 14 in 1990. High- β P experiments were explored by DIII-D 58 in the 2000s and have been extensively investigated since 2013 by the joint DIII-D/EAST research team 15 . An ITB at large minor radius is the signature of the high- β P scenario in DIII-D. The latest physical understanding for developing such an ITB is through the reduced magnetic shear and sufficient α-stabilization effect 40 , 59 (magnitude of α MHD ). As α MHD   ∝   q 2   ∝   I p −2 , a relatively low plasma current and a broader current-density profile (having a higher q value and reduced magnetic shear at large radius) are beneficial for realizing ITB. DIII-D high- β P experiments usually begin with a lower I p flat top, aiming at q 95  ≈ 10 in the first phase of the discharge. An I p ramp-up or B T ramp-down can be used in the later phase of the discharge to reduce the experimental q 95 to a desired level, for example, 6–8. Edge perturbations, such as ELMs, active gas puffing and impurity injection have experimentally been found to trigger the formation of an ITB by creating a ‘low-(magnetic) shear detour’ at large radius, which gives access to the second stability regime. Experimentally, it has been found that an empirical β P threshold of between 1.7 and 1.9 in DIII-D can sustain a strong ITB at large radius 15 . Regarding the plasma shape and configuration, a double-null configuration and an inverted ITER-similar true single-null shape have been successfully tested in experiments. Despite the high q min (over 2) in experiments, the high- β P scenario exhibits good fast-ion confinement, which is usually found to be classical. The present understanding  2, high-β steady-state scenarios on DIII-D. Phys. Plasmas 22, 055904 (2015)." href="/articles/s41586-024-07313-3#ref-CR60" id="ref-link-section-d165894986e2335">60 , 61 indicates that: (1) The high- β P plasmas have a shorter slowing-down time (because of the high density) and lower ∇ β fast , where β fast is the ratio of volume-averaged fast-ion pressure to the pressure of the toroidal magnetic field, which reduces the drive for Alfvénic modes. (2) The reverse-shear Alfvén eigenmodes are weaker or stable because the negative magnetic shear region is at higher radius, away from the peak of the fast-ion profile. Additionally, independent modelling of a high q min (over 2) ITER 8 MA steady-state scenario (not the high- β P scenario) found that there was negligible fast-ion loss because of a mismatch between the loss boundaries and the locations of the Alfvén eigenmodes 62 . A more detailed description of experimental waveform designs and a comprehensive review of the high- β P scenario development on DIII-D in the last decade can be found in a review paper 15 .

Diagnostics for profiles

A multi-pulsed high-resolution Thomson scattering system 63 , 64 was used to measure the core electron density and temperature in the DIII-D experiments. The ion temperature and the carbon density profiles were measured by a charge-exchange recombination spectroscopy system for C 6+ particles 65 . The measurements were arranged radially on the low-field side.

Statistical analysis

Our statistical analysis used experimental data from DIII-D discharges during 2019–2022. We recorded data pairs of ( f Gr , H 98y2 ) from two time slices for each discharge: (1) the highest H 98y2 and the corresponding f Gr at the same time and (2) the highest f Gr and the corresponding H 98y2 at the same time, unless the two time slices were the same. Several filters were applied: I p  ≥ 0.55 MA, d I p /d t  < 0.5 MA s −1 , P tot  ≥ 5 MW, W  ≥ 500 kJ and (d W /d t )/ P tot  ≤ 0.1. Here, W is the total energy stored by the plasma and P tot is the total heating power. A smoothing window of 40 ms was applied. The minimum and maximum H 98y2 values were truncated at 0.5 and 2.5, respectively. More than 3,600 discharges from 2019–2022 were used in the analysis.

Reconstruction of the kinetic equilibria

A multi-step workflow was used to add constraints on the pressure and plasma-current density in the equilibrium reconstruction to improve the accuracy of the reconstructed equilibrium. The workflow (for one iteration) has three parts: fitting the profile based on the existing equilibrium, calculating the power balance for the total pressure and plasma-current components, and reconstructing the equilibrium with pressure and current-density constraints. Usually, two or three iterations would be sufficient to produce high-quality equilibria for the transport study. When performing power balance calculation, NUBEAM 66 was used for the NBI-driven current and fast-ion pressure calculation, and the Sauter model 67 was used for the bootstrap current calculation. ONETWO 68 was used to create the total pressure by combining the thermal pressure and fast-ion pressure and to provide the total plasma-current density by considering the external driven current, the bootstrap current and the calculated Ohmic current and by solving the poloidal field diffusion. The equilibrium was reconstructed with the EFIT code 69 .

Gyro-fluid transport modelling

The TGLF code 38 was used to calculate the turbulent heat fluxes in the high- β P case and the low- q 95 H-mode case. This modelling used a more recent saturation rule, SAT2 (ref. 70 ). Electromagnetic effects were included. The modelling took an experimental kinetic equilibrium from one time slice and focused on one radial location, for example, ρ  = 0.65. The turbulent heat fluxes were predicted based on the local parameters of the selected time and radial location by taking contributions from several turbulent modes (low k and high k ) into account. Quasi-neutrality was maintained when scanning the local density gradient F p , meaning that the density gradients for all species changed accordingly. When scanning the local q , other quantities that are not independent of q were scanned accordingly. When scanning β e , the entire plasma β was changed accordingly, as T i / T e and n i / n e were fixed in the modelling.

Pedestal modelling

The ELITE code 41 was used to calculate the growth rate of the peeling–ballooning mode instability, which is believed to limit the achievable pedestal height by triggering ELMs when the plasma crosses the instability boundary. ELITE uses reconstructed equilibria with pressure and current constraints (kinetic equilibria) as input. On the basis of the input, a set of equilibria were generated by independently varying the edge pressure and current in a separate ELITE calculation to obtain the peeling–ballooning boundary.

The reduced three-field fluid module under the BOUT++ framework 42 , 43 , 44 was used to simulate the edge modes. The simulation evolved several physics parameters: perturbed pressure, magnetic flux and vorticity. The three-field module included not only basic peeling–ballooning physics but also non-ideal effects, such as ion diamagnetic drift, E  ×  B drift, resistivity and so on. The simulation domain in the normalized poloidal flux was 0.80 <  ψ N  < 1.05 and the grid resolution was n ψ  = 512 and n y  = 64. The kinetic equilibria were used as input. The Spitzer–Härm resistivity η Sp was used by considering realistic plasma kinetic profiles. The hyper-resistivity was taken as a constant value η H  = 10 −16 in the generalized Ohm’s law for current diffusion. The radial electric field ( E r ) profile calculated from the ion momentum balance equation was used in the simulation.

Data availability

Raw data were generated by the DIII-D team. The data that support the findings of this study are available from the corresponding author upon request.

Code availability

The computational codes used in the analysis of this paper are managed by General Atomics. They are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank the DIII-D team and the joint DIII-D/EAST research team for their support in the machine operation and data analysis and modelling. We express our deep gratitude to E. J. Strait of General Atomics for his suggestions on improving the manuscript text. Additionally, we thank M. T. Kotschenreuther of ExoFusion for insightful discussions on transport physics, which contributed significantly to the development of this work. This work is supported by the US Department of Energy (Grant Nos. DE-SC0010685, DE-FC02-04ER54698, DE-AC52-07NA27344, DE-FG02-04ER54761, DE-AC02-09CH11466 and DE-SC0016154). This report was prepared as an account of work sponsored by an agency of the United States Government. Neither the United States Government nor any agency thereof, nor any of their employees, makes any warranty, express or implied, or assumes any legal liability or responsibility for the accuracy, completeness, or usefulness of any information, apparatus, product, or process disclosed, or represents that its use would not infringe privately owned rights. Reference herein to any specific commercial product, process, or service by trade name, trademark, manufacturer, or otherwise, does not necessarily constitute or imply its endorsement, recommendation, or favoring by the United States Government or any agency thereof. The views and opinions of authors expressed herein do not necessarily state or reflect those of the United States Government or any agency thereof.

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Contributions

S.D. and A.M.G. conceived the experimental idea regarding DIII-D. S.D. led the experimental demonstration and conducted the DIII-D database analysis, equilibrium reconstructions, gyro-fluid transport modelling and writing the manuscript. A.M.G. provided guidance during the writing of the manuscript. H.Q.W. performed the pedestal stability and divertor condition analysis and provided the target low-q 95 discharge for analysis. Z.Y.L. performed the pedestal modelling. S.D., A.M.G., H.Q.W., X.J., L.W., X.Z.G., J.P.Q., J.H., J.M. and C.T.H. participated in designing and executing the experiments. D.B.W., D.E., B.S.V., A.M., Q.M.H., I.S.C., T.O., A.W.H., T.H.O. and J.M.H. participated in executing the experiments. T.O. conducted the impurity analysis. All authors reviewed the manuscript. A.M.G. and C.T.H. polished the manuscript.

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Extended data figures and tables

Extended data fig. 1 additional time histories for diii-d # 190904..

(a) Plasma current in blue and toroidal field in green; (b) Line-averaged density in blue and stored energy in green; (c) On-axis electron density in blue, on-axis deuterium density in green and on-axis carbon density in violet; (d) Measured neutron rate; (e) Injected NBI power in blue, measured total radiated power in green and core radiated power in violet.

Extended Data Fig. 2 Additional profiles for DIII-D # 190904.

Deuterium density profiles in (a), ratio between carbon density and electron density in (b) and safety factor profiles (q-profiles) in (c). Different color indicates the time slice shown in Fig. 2a . Additionally, profiles for a pre-ITB time slice (1.89 s) shown in gray dashed line are added.

Extended Data Fig. 3 Spatial and temporal evolution of electron temperature at the divertor plates, measured by Langmuir probes.

ψ N is normalized poloidal flux. ψ N  < 1.0 locates within the private flux region. Color coding shows the measured T e,div . Dashed lines indicate the actual positions of Langmuir probes.

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Ding, S., Garofalo, A.M., Wang, H.Q. et al. A high-density and high-confinement tokamak plasma regime for fusion energy. Nature (2024). https://doi.org/10.1038/s41586-024-07313-3

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The relationship between T7-Fz alpha coherence and peak performance in self-paced sports: a meta-analytical review

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We examined whether the alpha-band coherence between the T7-Fz (verbal analytical-motor planning) brain areas were related to superior performance in sports. We searched for related papers across eight databases: ProQuest Central, ProQuest Psychology Journals, PsycARTICLES, PsycINFO, SPORTDiscus, MEDLINE, Scopus, and Web of Science using relevant keywords (i.e., EEG AND sports AND coherence). Seven studies, with a total of 194 participants, met our inclusion criteria and were shortlisted for statistical analysis. We compared EEG coherence data for both within-subject and between-subject experimental designs. Our analysis revealed that athletes had lower coherence in the T7-Fz brain pathway for alpha- band activation (Hedges’ g  = − 0.54; p  = 0.03) when performing better. Theoretically, these results corroborate the notion that athletes become more “neurally efficient” as the verbal and motor areas of their brains function more independently, i.e., the neural efficiency hypothesis. Accordingly, athletes who can limit verbal interference are more likely to perform a sporting task successfully.

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Raman, D., Filho, E. The relationship between T7-Fz alpha coherence and peak performance in self-paced sports: a meta-analytical review. Exp Brain Res (2024). https://doi.org/10.1007/s00221-024-06833-8

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• Jinxia Liu 1 , 2 ,
• Jane MacNaughtan 1 ,
• Annarein J C Kerbert 1 ,
• Theo Portlock 3 ,
• Javier Martínez Gonzalez 4 , 5 ,
• Frederick Clasen 3 ,
• Abeba Habtesion 1 ,
• Huoyan Ji 6 ,
• Qin Jin 7 ,
• Alexandra Phillips 1 ,
• Francesco De Chiara 1 ,
• Ganesh Ingavle 8 , 9 ,
• Cesar Jimenez 5 ,
• http://orcid.org/0000-0002-3219-6963 Giacomo Zaccherini 10 , 11 ,
• Katherine Husi 12 ,
• Miguel Angel Rodriguez Gandia 13 ,
• Paul Cordero 9 ,
• Junpei Soeda 1 ,
• Lynda McConaghy 14 ,
• Jude Oben 1 ,
• Karen Church 14 ,
• Jia V Li 15 ,
• Haifeng Wu 2 ,
• Aarti Jalan 16 ,
• Pere Gines 17 ,
• Elsa Solà 17 ,
• Simon Eaton 18 ,
• Carrie Morgan 14 ,
• Michal Kowalski 14 ,
• Daniel Green 14 ,
• Amir Gander 19 ,
• http://orcid.org/0000-0002-8222-4555 Lindsey A Edwards 20 , 21 ,
• I Jane Cox 22 , 23 ,
• Helena Cortez-Pinto 24 ,
• Thomas Avery 25 ,
• Reiner Wiest 26 ,
• Francois Durand 27 ,
• Paolo Caraceni 10 , 28 ,
• Roberto Elosua 29 ,
• Joan Vila 29 ,
• Marco Pavesi 30 ,
• Vicente Arroyo 30 ,
• Nathan Davies 1 ,
• Rajeshwar P Mookerjee 1 ,
• Victor Vargas 5 ,
• Susan Sandeman 8 ,
• http://orcid.org/0000-0002-5696-359X Gautam Mehta 1 ,
• Saeed Shoaie 3 ,
• Julian Marchesi 31 ,
• http://orcid.org/0000-0001-9131-2592 Agustín Albillos 32 ,
• Fausto Andreola 1 ,
• http://orcid.org/0000-0002-7747-4015 Rajiv Jalan 1 , 30
• 1 Liver Failure Group , UCL Institute for Liver & Digestive Health, Division of Medicine , London , UK
• 2 Department of Gastroenterology , Affiliated Hospital of Nantong University , Nantong , Jiangsu , China
• 3 Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences , King’s College London , London , UK
• 4 Hospital Ramón y Cajal, IRYCIS, CIBEREHD, Universidad de Alcalá , Madrid , Spain
• 5 Liver Unit, Hospital Vall d’Hebron, Universitat Autónoma, CIBERehd , Barcelona , Spain
• 6 Department of Laboratory Medicine , Affiliated Hospital of Nantong University , Nantong , China
• 7 Department of Pathology , Affiliated Hospital of Nantong University , Nantong , China
• 8 Centre for Regenerative Medicine and Devices, School of Applied Sciences , University of Brighton , Brighton , UK
• 9 Symbiosis Centre for Stem Cell Research (SCSCR), Symbiosis School of Biological Sciences (SSBS), Symbiosis International (Deemed University) , Pune , India
• 10 Department of Medical and Surgical Sciences , University of Bologna , Bologna , Italy
• 11 Unit of Semeiotics, Liver and Alcohol-related Diseases , University of Bologna Hospital of Bologna Sant'Orsola-Malpighi Polyclinic , Bologna , Italy
• 12 Department of Gastroenterology , Inselspital University Hospital Bern , Bern , Switzerland
• 13 Hospital Universitario Ramon y Cajal , Madrid , Spain
• 14 Yaqrit Discovery Limited. The Elms Courtyard, Bromesberrow , Ledbury , UK
• 15 Department of Surgery and Cancer , Imperial College London , London , UK
• 16 King's College Hospital , London , UK
• 17 Liver Unit, Hospital Clinic of Barcelona, IDIBAPS, Faculty of Medicine and Health sciences , University of Barcelona , Barcelona , Spain
• 18 Institute of Child Health , University College London , London , UK
• 19 Tissue Access for Patient Benefit , University College London , London , UK
• 20 Centre for Host Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, Guy's Tower, Guy's Hospital , King’s College London , London , UK
• 21 Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine , King’s College London , London , UK
• 22 The Roger Williams Institute of Hepatology, Foundation for Liver Research , London , UK
• 23 Faculty of Life Sciences and Medicine, King's College London , London , UK
• 24 Clínica Universitária de Gastrenterologia, Laboratório de Nutrição, Faculdade de Medicina, Universidade de Lisboa , Lisbon , Portugal
• 25 Yaqrit Limited , London , UK
• 26 UVCM Gastroenterology , University Bern , Bern , Switzerland
• 27 Hepatology and Liver Intensive Care , Hospital Beaujon, Clichy, University paris Cité , Paris , France
• 28 Unit of Semeiotics, Liver and Alcohol Related Diseases , IRCCS Azienda Ospedaliero-Universitaria di Bologna , Bologna , Italy
• 29 C/de Joan Güell , Barcelona , Spain
• 30 European Foundation for the Study of Chronic Liver Failure (EF CLIF) , Barcelona , Spain
• 31 Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction , St Mary’s Hospital, Imperial College London , London , UK
• 32 Department of Gastroenterology and Hepatology, Hospital Universitario Ramon y Cajal, Universidad de Alcalá, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) , Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD) , Madrid , Spain
• Correspondence to Professor Rajiv Jalan, UCL Institute for Liver & Digestive Health, London NW3 2PF, UK; r.jalan{at}ucl.ac.uk

Objective Targeting bacterial translocation in cirrhosis is limited to antibiotics with risk of antimicrobial resistance. This study explored the therapeutic potential of a non-absorbable, gut-restricted, engineered carbon bead adsorbent, Yaq-001 in models of cirrhosis and acute-on-chronic liver failure (ACLF) and, its safety and tolerability in a clinical trial in cirrhosis.

Design Performance of Yaq-001 was evaluated in vitro . Two-rat models of cirrhosis and ACLF, (4 weeks, bile duct ligation with or without lipopolysaccharide), receiving Yaq-001 for 2 weeks; and two-mouse models of cirrhosis (6-week and 12-week carbon tetrachloride (CCl4)) receiving Yaq-001 for 6 weeks were studied. Organ and immune function, gut permeability, transcriptomics, microbiome composition and metabolomics were analysed. The effect of faecal water on gut permeability from animal models was evaluated on intestinal organoids. A multicentre, double-blind, randomised, placebo-controlled clinical trial in 28 patients with cirrhosis, administered 4 gr/day Yaq-001 for 3 months was performed.

Results Yaq-001 exhibited rapid adsorption kinetics for endotoxin. In vivo , Yaq-001 reduced liver injury, progression of fibrosis, portal hypertension, renal dysfunction and mortality of ACLF animals significantly. Significant impact on severity of endotoxaemia, hyperammonaemia, liver cell death, systemic inflammation and organ transcriptomics with variable modulation of inflammation, cell death and senescence in the liver, kidneys, brain and colon was observed. Yaq-001 reduced gut permeability in the organoids and impacted positively on the microbiome composition and metabolism. Yaq-001 regulated as a device met its primary endpoint of safety and tolerability in the clinical trial.

Conclusions This study provides strong preclinical rationale and safety in patients with cirrhosis to allow clinical translation.

Trial registration number NCT03202498 .

• BACTERIAL TRANSLOCATION
• LIVER CIRRHOSIS
• LIVER FAILURE

Data availability statement

Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information.

https://doi.org/10.1136/gutjnl-2023-330699

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WHAT IS ALREADY KNOWN ON THIS TOPIC

Current strategies to target bacterial translocation in cirrhosis are limited to antibiotics with risk of resistance.

WHAT THIS STUDY ADDS

Yaq-001 rapidly adsorbs endotoxin, ammonia and bile acids and impacts positively on markers of gut permeability, liver injury, fibrosis, portal pressure, brain and kidney dysfunction in animal models of cirrhosis and reduces mortality from acute-on-chronic liver failure.

In models of cirrhosis, Yaq-001 restores microbiome composition and reduces endotoxaemia, ammonia, severity of inflammation, liver cell death, signalling pathways and lipopolysaccharide sensitivity.

Enhanced permeability of intestinal organoids following incubation with faecal water from cirrhosis animals is prevented by Yaq-001.

In a multicentre, double-blind, randomised, placebo-controlled clinical trial of Yaq-001 versus placebo in patients with cirrhosis, Yaq-001 was found to be safe and well tolerated.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

The data provide the preclinical rationale and clinical safety to proceed to the next phase of clinical trials in patients with cirrhosis aiming to prevent the occurrence of complications.

Introduction

Gut dysbiosis and gut-derived bacterial ligands, in particular endotoxin, drive a dysregulated inflammatory response, which has been implicated in the development of cirrhosis and its complications such as sepsis, spontaneous bacterial peritonitis, renal dysfunction and hepatic encephalopathy. 1–3 This dysregulated inflammatory response is also central to the development of acute-on-chronic liver failure (ACLF). 4 Markers of bacterial translocation such as endotoxin and bacterial DNA have been shown to be associated with complications of cirrhosis and diminished survival highlighting their pathogenic importance. 5–7 The microbiome in cirrhosis is characterised by reduced diversity and abundance of autochthonous bacteria. 1 While antibiotics have been shown to impact positively on complications of cirrhosis, their use is associated with antibiotic resistance. 8 9 Furthermore, antibiotics reduce bacterial diversity rendering the microbiome less resilient.

One of the consequences of bacterial translocation in cirrhosis is that the endotoxin-sensing pathways in different organs are known to be primed resulting in heightened susceptibility to organ injury. 3 10 Adsorption of free endotoxin without exerting direct effects on bacterial growth kinetics, therefore, has the potential to attenuate susceptibility to organ injury without producing the deleterious effects on the microbiome. Considering this, we developed a synthetic non-absorbable, non-antibiotic, endotoxin sequestrant and generated the hypothesis that this may be a novel therapeutic strategy to restore the microbiome, prevent bacterial translocation, systemic inflammation progression of fibrosis and cirrhosis complications. Yaq-001 is a gut-restricted, non-absorbable, highly engineered, activated carbon of multiple porosities tailored to the micro (<2 nm) and meso-macroporous (30–200 nm) range and has a high surface area. 11–13 These properties confer a high adsorptive capacity for larger biologically relevant molecules such as bacterial toxins in addition to smaller intraluminal targets. The most closely associated experimental oral adsorbent is AST-120, a microporous carbon bead, which has not been shown to be efficacious in patients with hepatic encephalopathy. 14

In this study, we sought to determine the adsorptive capacity of Yaq-001 and its effect on bacterial growth kinetics in in vitro studies. We then evaluated the in vivo biological effects of Yaq-001 in four animal models representing characteristics of fibrosis, cirrhosis and ACLF. We studied the effects of Yaq-001 on measures of multiorgan function, systemic and portal haemodynamics, immune function, multiorgan transcriptomics and microbiome composition. Finally, we performed a phase 2 equivalent, multicentre, double-blind, randomised, placebo-controlled clinical trial to assess the safety and tolerability of Yaq-001 in patients with decompensated cirrhosis.

Methodological details are described in online supplemental section .

Supplemental material

Functional and structural characteristics of yaq-001.

Adsorption of biomolecules of varying molecular weights (albumin, myoglobin and caffeine) was evaluated. Bacterial growth was studied for Staphylococcus aureus and Escherichia coli . Scanning electron microscopy was performed to characterise the beads and pore size distribution was assessed using mercury porosimetry.

Studies in animal models

Study design.

These studies aimed to characterise the therapeutic potential of Yaq-001 in rats and mice models to define its role in prevention of occurrence of cirrhosis, progression of cirrhosis and occurrence of ACLF ( online supplemental figures S1 and S2 ).

Animal models

Four-week bile-duct ligation model of advanced fibrosis.

Cirrhosis: Sham (n=36); Sham-Yaq-001 (n=30); bile duct ligation (BDL) (n=37); BDL-Yaq-001 (n=44).

Prevention of ACLF: Sham-lipopolysaccharide (LPS) (n=9); Sham-LPS-Yaq-001 (n=10); BDL-LPS (n=16); BDL-LPS-Yaq-001 (n=12).

Yaq-001 (0.4 g/100 g body weight per day) was administered for 2 weeks prior to sacrifice. At the time of sacrifice, mean arterial pressure (MAP) and portal pressure were measured.

Carbon tetrachloride treated model of cirrhosis

Advanced fibrosis and early cirrhosis (CCl4 for 6 weeks): control (n=6); control-Yaq-001 (n=6); CCl4 (n=12); CCl4-Yaq-001 (n=12).

Advanced cirrhosis (CCl4 for 12 weeks): control (n=6); control-Yaq-001 (n=6); CCl4 (n=12); CCl4-Yaq-001 (n=12).

Yaq-001 (0.4 g/100 g body weight per day) was administered from 0 to 6 weeks in the 6-week model and from 6 to 12 weeks in the 12-week model.

Collection and analysis of biosamples

Blood, stool and tissue samples were collected for later analysis. Portal venous blood was collected where possible. Peripheral blood cells and Kupffer cell reactive oxidant species (ROS) were measured. H&E, picrosirius red (PSR) staining and TUNEL stains were performed in liver tissues. The mRNA in different organs was analysed by using nSolver V.4.0 software (NanoString Technologies). To define effect on the microbiome, 16s microbiome study was performed. To determine the effect of Yaq-001 on modulating metabolism, urinary 1 H-NMR analysis was performed.

Assessment of gut permeability in intestinal organoids

Permeability of mouse intestinal organoids was detected using established protocols. 15 16 Faecal water generated from the stools obtained from the four groups of 6-week CCl4 mice was incubated with the organoids. 15 16 Permeability of the organoids was assessed.

Clinical trial of Yaq-001 versus placebo, CARBALIVE-SAFETY study

The CARBALIVE-SAFETY clinical trial was a first in man, multicentre, double-blind, randomised, placebo-controlled clinical trial of oral Yaq-001 in decompensated cirrhosis. Details of the study protocol are available in online supplemental section (CONSORT, online supplemental figure S3 ). As Yaq-001 is regulated as a device, it followed both ISO standards and ICH-GCP guidance. Informed consent was obtained from each patient. The study was closely monitored and overseen by an independent data safety monitoring board ( NCT03202498 ).

Study design is described as online supplemental figure S4 . The primary endpoint was assessed at 12 weeks. Blood and stool samples were taken at the time of randomisation, 4 weeks and 12 weeks for assessment of some of the secondary and exploratory endpoints. Safety assessments were performed on weeks 1, 4, 8 and 12 and comprised a physical examination, clinical laboratory tests, urinalysis, 12-lead ECG and an assessment of reported and observed adverse events. ECGs were analysed independently. Nutritional status was assessed by the Royal Free Hospital Global Assessment tool at each safety assessment together with micronutrient analysis at baseline, weeks 4 and 12. Vitamin B 12 , A, D, E, folate, and K1 and, trace elements copper, zinc and selenium were analysed.

Main inclusion and exclusion criteria

The main inclusion criteria were participants aged 18 years or above, clinical diagnosis of diuretic-responsive cirrhotic ascites (Child-Pugh score=7–11 inclusive), abstinence from alcohol for at least 4 weeks prior to screening and written informed consent. The main exclusions were lack of informed consent, use of oral antibiotics, immunosuppressants or antiviral medication within 4 weeks prior to recruitment, change in dose of proton pump inhibitor therapy within 4 weeks before the start of the study treatment, hospital admission for liver-related indication for at least 4 weeks (except paracentesis), body mass index (BMI) >35 or BMI<18 kg/m 2 and the presence of a transjugular intrahepatic portosystemic shunt (see protocol in online supplemental file for details).

Randomisation, dosing and compliance

Patients were randomised 1:1 to receive 4 g of oral Yaq-001 or equivalent placebo nocte after dinner for 12 weeks. The interval between Yaq-001 and concomitant medication administration was 4 hours treatment compliance was assessed by the number of used or unopened sachets returned to the clinical site at each visit. Patients taking ≥70% of study medication were considered compliant.

Endpoints and assessments

Primary endpoints.

The main objective of this clinical investigation was to assess the safety and tolerability of Yaq-001 throughout the 3 months’ treatment period.

Secondary and exploratory endpoints

Blood and stool samples were collected for later analysis for markers of endotoxemia, systemic inflammation, bile acids, short-chain fatty acids, gut permeability and the microbiome (results not reported in this paper).

Statistical analysis

Animal studies.

Based on the in vitro studies, we anticipated a 50% decrease in circulating endotoxin in the treatment groups with an alpha error of 0.05 and power of 80%, resulting in a minimum sample size of 5 animals/group. As this study included several pathophysiological endpoints, multiple experimental groups were included. All the data accrued from these studies are described in this paper. All the rats in eight groups from three independent batches were included in the analysis as shown in online supplemental figure S1 . All the mice studied in eight groups were included in online supplemental figure S2 .

Group comparisons for continuous variables were performed using Man-Whitney U test (no-normal distribution) or unpaired t-test (normal distribution) and for categorical variables by using χ 2 test. The data were analysed using R package (R V.4.4.4). 16s microbiome study and circos correlation were analysed by using Wilcoxon rank sum test and Spearman correlation. Software used Graphpad Prism V.9.0 (GraphPad software, San Diego, California, USA).

CARBALIVE-SAFETY clinical trial

This first-in-man clinical investigation was not powered to demonstrate statistical significance for any endpoint. All statistical analyses of study data were carried out using SAS V.9.3 or a later version. For categorical variables, summary tabulations of the number and percentage of patients within each category (with a category for missing data) of the parameter are presented. Percentage calculations are based on non-missing data unless otherwise specified. Please also see protocol ( online supplemental file ).

Yaq-001 beads exhibited a consistent predefined structure with a bead diameter within the 250–500 µm range and the prescribed porosity ( online supplemental figure S5A ). Yaq-001 rapidly adsorbed albumin (66.5 kDa), myoglobin (16.7 kDa) and caffeine (0.194 kDa) representing different sized biomolecules ( online supplemental figure S5B ). Yaq-001 adsorbed LPS (18 kDa) reducing the concentrations from 2.5 to 1.5 EU/mL (60%) within 30 min. No endotoxin was detected in the control solution (0 EU/mL) ( online supplemental figure S5B ). Yaq-001 also adsorbed a range of bile acids ( online supplemental figure S5C ). Direct coincubation of Yaq-001 with bacterial suspensions of either E. coli or S. aureus indicated that Yaq-001 did not affect bacterial growth kinetics for either species following direct contact in comparison to the antibiotic controls ( online supplemental figure S5D ). Mercury porosimetry showed that Yaq-001 used in the clinical trial had a consistent pore size distribution plot in the meso-macroporous range from 30 to 200 nm ( online supplemental figure S5E ).

Yaq-001 exhibited better performance in adsorptive capacity and effect on endotoxin kinetics than AST-120 (Kremezin, Kureha, Japan) ( online supplemental figure S5 ).

Studies in BDL rat model of advanced fibrosis

Effect of yaq-001 on liver injury and portal pressure.

BDL rat model was used to assess the effect of Yaq-001 in cirrhosis ( figure 1A ). Significant reduction in 4-week body weight was observed in BDL rats (p<0.0001), which was prevented by administration of Yaq-001 (p=0.045) ( figure 1A ). Yaq-001 was associated with a significantly lower plasma ALT (p=0.007). ALP, TBIL and albumin were not impacted by Yaq-001 ( online supplemental figure S6A–C ). Total bile acid concentrations were not different between the BDL and Sham groups and there was no significant impact of Yaq-001 ( online supplemental figure S6E ). Mean arterial pressure (MAP) was lower in BDL animals and no effect of Yaq-001 was observed ( online supplemental figure S6F ). Yaq-001 resulted in a significant reduction in portal pressure compared with untreated BDL rats ((median (IQR) 11.1 mm Hg (10.3–11.7) vs 12.4 mm Hg (10.8–13.3), (p=0.025)) ( figure 1A ). TUNEL assay showed significantly more intense staining in the liver tissue of BDL compared with Sham rats ( figure 1A ) (p<0.0001), which were significantly reduced in Yaq-001-treated BDL rats compared with untreated-BDL rats (p=0.025). Collagen proportionate area (CPA) was significantly higher in BDL rats (p=0.0007) compared with Sham rats, which was unchanged with Yaq-001 (p=0.122) ( online supplemental figure S6D ).

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Effect of Yaq-001 on organ dysfunction, endotoxaemia and bacterial translocation in BDL and ACLF rats. (A) Rats underwent bile duct ligation for 4 weeks as a model of cirrhosis (n=23–37/group). Treatment groups received Yaq-001 for 2 weeks before sacrifice. (A) 4-week body weight in four groups: Sham (n=31), Sham-Yaq-001 (n=24), BDL (n=31) and BDL-Yaq-001 (n=38). Significantly lower final body weights were observed in BDL compared with Sham controls (p<0.001). Yaq-001-treated BDL rats had a significantly higher body weights compared with untreated-BDL rats (p<0.05). Plasma alanine transaminase (ALT) concentrations in Sham (n=17), Sham-Yaq-001 (n=14), BDL (n=17) and BDL-Yaq-001 (n=26) groups and Portal pressure (PP) measurements in Sham (n=17), Sham-Yaq-001 (n=19), BDL (n=14) and BDL-Yaq-001 (n=26) groups. Significantly higher ALT and PP were observed in BDL compared with Sham controls (p<0.0001). Yaq-001-treated BDL rats had a significantly lower ALT and PP compared with untreated-BDL rats (p<0.01, p<0.05). TUNEL assay of liver tissue with quantification of staining by digital image analysis. Significantly higher TUNEL staining was observed in BDL compared with Sham controls (p<0.0001). Yaq-001-treated BDL rats had a significantly lower TUNEL staining compared with untreated-BDL rats (p<0.05) indicative of a reduction in liver cell death with Yaq-001 treatment. Arterial ammonia concentrations in Sham (n=7), Sham-Yaq-001 (n=5), BDL (n=19), BDL-Yaq-001 (n=21) groups and Portal venous ammonia concentrations in Sham (n=6), Sham-Yaq-001 (n=5), BDL (n=13), BDL-Yaq-001 (n=18) groups. Significantly increased arterial ammonia concentrations and portal venous ammonia concentrations were observed in BDL compared with Sham controls (p<0.0001, p=0.0001). Yaq-001 significantly decreased arterial and portal venous ammonia concentrations in BDL rats (p<0.01 for both). Serum creatinine in Sham (n=19), Sham-Yaq-001 (n=17), BDL (n=20), BDL-Yaq-001 (n=17) and serum urea in Sham (n=28), Sham-Yaq-001 (n=23), BDL (n=30), BDL-Yaq-001 (n=34) groups. Yaq-001 markedly decreased serum creatinine levels in BDL rats (p<0.05). Plasma D-lactate in Sham (n=7), Sham-Yaq-001 (n=8), BDL (n=6), BDL-Yaq-001 (n=7). Plasma D-lactate was significantly increased in the BDL group compared with Sham animals (p<0.05). Yaq-001 resulted in a significant reduction in plasma D-lactate in BDL rats (p<0.05). Portal venous endotoxin (Sham (n=6), Sham-Yaq-001 (n=5), BDL (n=12) and BDL-Yaq-001 (n=7)) and arterial endotoxin (Sham (n=6), Sham-Yaq-001 (n=5), BDL (n=12) and BDL-Yaq-001 (n=7)). Portal venous bacterial DNA positivity (Sham (n=6), Sham-Yaq-001 (n=5), BDL (n=12) and BDL-Yaq-001 (n=13)) and arterial plasma bacterial DNA positivity (Sham (n=6), Sham-Yaq-001 (n=6), BDL (n=12) and BDL-Yaq-001 (n=7)). Significantly higher portal venous endotoxin and arterial endotoxin were observed in BDL rats compared with Sham rats (p<0.0001). Significantly higher portal venous plasma bacterial DNA positivity was observed in BDL rats compared with Sham rats (p<0.05). Yaq-001 administration was associated with a significant reduction of portal venous and arterial endotoxin compared with untreated-BDL rats (p<0.0001, p<0.01). Yaq-001 administration reduced bacterial DNA positivity, which was not statistically different (p>0.05). (B) Rats underwent sham biliary surgery or BDL for 4 weeks. The treated group received Yaq-001 for 2 weeks prior to LPS injection. Animals were sacrificed either at coma stages or 6 hours after LPS injection (n=9–16/group). Kaplan-Meier analysis of BDL-LPS rats with (n=16) or without (n=12) Yaq-001 treatment. Yaq-001 treatment significantly improved the survival of BDL-LPS rats compared with untreated-BDL-LPS rats (log rank test, p=0.003). Plasma ALT concentrations in Sham-LPS (n=7), Sham-LPS-Yaq-001 (n=5), BDL-LPS (n=10) and BDL-LPS-Yaq-001 (n=9) groups and portal pressure measurements in Sham-LPS (n=8), Sham-LPS-Yaq-001 (n=10), BDL-LPS (n=9) and BDL-LPS-Yaq-001 (n=9) groups. Yaq-001-treated BDL-LPS rats had a significantly lower ALT and potal pressure compared with untreated-BDL-LPS rats (p<0.005). Brain water percentage in Sham-LPS (n=4), Sham-LPS-Yaq-001 (n=4), BDL-LPS (n=7), BDL-LPS-Yaq-001 (n=13) groups. Arterial ammonia concentrations in Sham-LPS (n=5), Sham-LPS-Yaq-001 (n=5), BDL-LPS (n=7), BDL-LPS-Yaq-001 (n=7) groups. Portal venous ammonia concentrations in Sham-LPS (n=5), Sham-LPS-Yaq-001 (n=5), BDL-LPS (n=6), BDL-LPS-Yaq-001 (n=5) groups. Yaq-001 decreased brain water percentage and arterial/portal venous ammonia concentrations in BDL-LPS rats compared with untreated rats (p<0.05, p<0.01, p<0.05). Serum creatinine in Sham-LPS (n=4), Sham-LPS-Yaq-001 (n=3), BDL-LPS (n=12) and BDL-LPS-Yaq-001 (n=6) groups. Serum urea in Sham-LPS (n=8), Sham-LPS-Yaq-001 (n=4), BDL-LPS (n=12) and BDL-LPS-Yaq-001 (n=8) groups. Yaq-001 significantly decreased creatinine levels in BDL-LPS rats (p<0.05). Plasma cytokines in Sham-LPS (n=6), Sham-LPS-Yaq-001 (n=9), BDL-LPS (n=8) and BDL-LPS-Yaq-001 (n=8) groups. Yaq-001 significantly decreased plasma IL-1β and IL-10 concentrations in BDL-LPS groups (p<0.01, p<0.05). *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001. ACLF, acute-on-chronic liver failure; BDL, bile duct ligation; LPS, lipopolysaccharide.

Effect of Yaq-001 on ammonia, organ dysfunction, endotoxaemia and bacterial translocation

Ammonia: Arterial and portal venous ammonia concentrations were significantly increased in BDL rats (p<0.0001), which were significantly reduced by Yaq-001 ((p=0.003) and (p=0.004), respectively) ( figure 1A ). None of the animals showed signs of overt hepatic encephalopathy.

Kidneys: BDL animals had significantly higher plasma creatinine (p=0.049), which was significantly reduced with Yaq-001 (p=0.025) ( figure 1A ). Urea was higher in BDL group (p=0.092), which was reduced with Yaq-001 treatment (p=0.095) ( figure 1A ).

Gut permeability, endotoxaemia, bacterial DNA and cytokines: The microbial metabolite, D-lactate, a marker of gut-specific intestinal barrier damage and translocation 16 was significantly increased in BDL rats (p=0.032) and was significantly reduced by Yaq-001 (p=0.035) ( figure 1A ). BDL rats exhibited marked endotoxaemia in the portal vein and the artery (p<0.0001 for each), which was significantly reduced with Yaq-001 ((p<0.0001) (p=0.003), respectively) ( figure 1A ). Portal venous bacterial DNA was detectable in significantly higher number of BDL rats (p<0.05), which was markedly reduced in Yaq-001 administered BDL rats (p=0.08) ( figure 1A ). Plasma IL- β concentration was higher in the BDL rats but no significant differences were observed in TNF-a, IL-6 and IL-10. No significant changes were seen with Yaq-001 ( online supplemental table S1 ).

Studies in the BDL model of ACLF

This experiment was performed to determine whether Yaq-001 treatment for 2 weeks prevents the occurrence of ACLF when BDL animals are administered LPS ( online supplemental figure S1 , figure 1B ).

Survival: Animals were sacrificed either at coma stages (considered as a surrogate for mortality) or at 6 hours post-LPS. Yaq-001 significantly impacted on time to coma of BDL-LPS rats compared with untreated controls (p<0.01) ( figure 1B ). All animals in the two Sham groups were alive at 6 hours following LPS (data are not shown).

Liver: Yaq-001 was associated with significantly lower ALT in BDL-LPS rats compared with untreated rats (p=0.004) ( figure 1B ). No significant effect of Yaq-001 was observed on ALP, TBIL and albumin ( online supplemental figure S7A–C ). The severity of fibrosis measured using CPA and the body weight was unchanged ( online supplemental figure S7D,E ).

Systemic and portal haemodynamics: No significant difference in MAP was observed between the groups treated with or without Yaq-001 ( online supplemental figure S7F ) but Yaq-001 produced a significant reduction in portal pressure in BDL-LPS animals compared with the untreated group (p=0.003), ( figure 1B ).

Brain: Yaq-001 significantly reduced brain water in BDL-LPS compared with the untreated group (p=0.017) ( figure 1B ). Arterial and portal venous ammonia concentrations were significantly increased in BDL-LPS rats, which were significantly reduced in Yaq-001-treated animals ((p=0.007) and (p=0.017) respectively) ( figure 1B ).

Kidneys: Creatinine concentration was significantly higher in BDL-LPS animals (p=0.004), which was significantly reduced by Yaq-001 (p=0.03) ( figure 1B ).

Cytokines: BDL-LPS group had a significantly higher plasma IL-1β, which was significantly reduced with Yaq-001 (p=0.003). Plasma IL-10 was higher in BDL-LPS and was significantly reduced with Yaq-001 (p=0.028) ( figure 1B ). No significant differences were observed in IL-6 or TNF-α concentrations between any of the groups ( online supplemental table S1 ).

Effect of Yaq-001 on peripheral blood cells and Kupffer cells

Significant increase in total leucocyte, neutrophil and monocyte counts in the artery and portal vein was observed with BDL rats ( online supplemental figure S8A,B ) (p=0.008 and p=0.016, respectively), which were significantly reduced with Yaq-001 in the arterial blood and insignificantly reduced in the portal vein ( online supplemental figure S8B ). To determine whether Yaq-001 impacts on the response of peripheral inflammatory cells and Kupffer cells to generate reactive oxygen species (ROS) to LPS ex vivo, studies using isolated cells incubated with LPS, were performed. Yaq-001 was associated with significantly lower LPS-induced ROS production in CD163− Kupffer cells in BDL rats (p=0.036) and portal venous CD43 hi monocyte populations of BDL rats (p=0.029) ( online supplemental figure S8C ).

Transcriptomic analysis of gene expression profiles from the liver, colon, brain and kidneys

Multiorgan transcriptomic analysis was performed to determine the possible molecular mechanisms underlying the clinical effects of Yaq-001. The four groups studied were as follows: Sham (n=3), Sham-Yaq-001 (n=3), BDL (n=3) and BDL-Yaq-001 (n=4) ( figure 2A ). All differentially expressed genes (DEGs) and related pathways in the liver, colon, kidney and brain are listed in online supplemental table S2 . The top 20 and significant DEGs are listed in online supplemental table S3 .

Effect of Yaq-001 on gene expression profiles in the liver and extrahepatic organs in BDL rats. (A) Rats underwent BDL for 4 weeks as a model of cirrhosis (n=3–4/group) and the treatment groups received Yaq-001 for 2 weeks before sacrifice. Liver, colon, brain and kidney were collected for transcriptomic analysis. (B, D, F, H) Heatmap of differentially expressed genes (DEGs) in different organs between Sham (n=3), Sham-Yaq-001 (n=3), BDL (n=3) and BDL-Yaq-001 (n=4) groups. DEGs were identified at 1.2-fold change and p=0.1 threshold in three pairwise groups (BDL vs Sham, BDL-Yaq-001 vs BDL, Sham-Yaq-001 vs Sham). (C, E, G, I) Volcano plot of pairwise DEGs in four organs among Sham (n=3), Sham-Yaq-001 (n=3), BDL (n=3) and BDL-Yaq-001 (n=4) groups. The vertical dashed lines indicated the threshold for 1.2-fold change. The horizontal dashed line indicated the adjusted p=0.05 and p=0.1 threshold. The right part indicates upregulation of gene expression, and the left part indicates downregulation of gene expression. For top 20 genes indicated by gene names, please see online supplement Table 3. BDL, bile duct ligation.

Effect of Yaq-001 on gene expression profiles in the liver and gut in BDL rats

Liver: Analysis of liver tissue showed 82 DEGs at the threshold of 1.2-fold change and p=0.1 in the four groups ( figure 2B ). Compared with the Sham group, expression of 62 genes was upregulated, and 15 genes were downregulated in BDL. These significantly changed genes were associated with inflammation, cell death and senescence. Compared with the untreated BDL group, the expression of 7 genes was upregulated and 12 genes were downregulated in the Yaq-001-treated BDL group, indicating the potential role of Yaq-001 in reducing inflammation, cell death and cellular senescence. Furthermore, two genes were upregulated, and four genes were downregulated in Sham-Yaq-001 group in comparison to Sham group ( figure 2C ). Functional analysis demonstrated that BDL rats had enriched pathways related to inflammation, cellular senescence, cell death, TLR signalling and other related signalling pathways in comparison with Sham ( online supplemental figure S9A ). Yaq-001 treatment targeted the altered pathways compared with untreated BDL group. Additionally, Yaq-001 treatment also changed the pathways in the liver when compared with Sham group, demonstrating its effect in rats even without cirrhosis ( online supplemental figure S9A ).

Colon: 43 DEGs were identified from the colonic tissue ( figure 2D ). Five genes that correlated with inflammation and cell death were upregulated and 15 genes were downregulated in BDL compared with the Sham group. Moreover, the expression of 10 genes were upregulated, and 13 genes were downregulated with Yaq-001 treatment. Only 1 gene was upregulated in the Sham-Yaq-001 group, and 16 genes were downregulated with Yaq-001 compared with the untreated Sham group ( figure 2E ). Functional analysis indicated that inflammation, cellular senescence, cell death, TLR signalling and intracellular signalling were associated with BDL in comparison with the Sham group ( online supplemental figure S9B ). Yaq-001 targeted the altered pathways, indicating the potential mechanisms in the prevention of gut dysfunction and permeability ( online supplemental figure S9B ).

Effect of Yaq-001 on gene expression profiles in the brain and kidney in BDL rats

Brain: 17 DEGs were identified from the brain tissue ( figure 2F ). Compared with Sham group, expression of 2 genes were upregulated and 13 genes were downregulated in BDL animals. These significantly changed genes were associated with inflammation, cell death and cellular senescence. Compared with the untreated-BDL group, the expression of five genes were upregulated and two genes were downregulated in the Yaq-001-treated BDL group ( figure 2G ). Functional analysis demonstrated that BDL rats had enriched pathways related to inflammation, cellular senescence, cell death, TLR signalling and intracellular signalling ( online supplemental figure S9C ). Yaq-001 targeted cytokine–cytokine receptor interaction, cytosolic DNA-sensing pathway, TLR signalling pathway, NOD-like receptor signalling pathway, neutrophil extracellular trap formation, TGF-beta signalling pathway and cytokine-cytokine receptor interaction pathways compared with untreated-BDL group ( online supplemental figure S9C ).

Kidneys: 30 DEGs were identified from kidney tissue ( figure 2H ). Nine genes that correlated with inflammation were downregulated in BDL. The expression of five genes was upregulated and four genes were downregulated with Yaq-001 treatment compared with untreated-BDL group. Five genes were upregulated in Sham-Yaq-001 group, and three genes were downregulated with Yaq-001 compared with untreated-Sham group ( figure 2I ). Functional analysis indicated that inflammation and TLR signalling were associated with BDL in comparison with Sham ( online supplemental figure S9D ). Compared with the untreated-BDL group, Yaq-001 targeted the altered pathways, indicating the potential mechanisms in the prevention of renal dysfunction ( online supplemental figure S9D ).

Effect of Yaq-001 on the gut microbiome profile

The effects of Yaq-001 on the microbiome bacterial composition were assessed by metataxonomics. At the family level, an abundance of six bacteria was significantly changed at the threshold of twofold change and Porphyomonadaceae was significantly changed (p<0.05) comparing BDL with Sham ( figure 3A ). At genus level, 19 bacteria were significantly changed in abundance. Barnesiella was significantly changed (p<0.05) comparing BDL with Sham group ( figure 3B ). These changes were reversed with Yaq-001 treatment compared with untreated-BDL rats ( online supplemental figure S10A,B , online supplemental table S4 and online supplemental figure S10C,D ). For between-groups sample diversity, PERMANOVA analysis revealed a significant difference in beta diversity between groups (R 2 =0.32, p=0.001). Yaq-001 appeared to moderately restore the beta diversity in the BDL group especially in PCoA2 axis ( online supplemental figure S10E,F ).

Effect of Yaq-001 treatment on the microbiome composition. (A) Heatmap of gut microbiome associated with the effect of Yaq-001 as determined by 16S PCR at the family level. The family Porphyromonadaceae with asterisk was statistically differently abundant between BDL (n=7) vs Sham (n=6), and between BDL-Yaq-001 (n=7) vs BDL groups (n=7) (Wilcoxon rank sum test, p<0.05). The abundance of this family was statistically higher in BDL group than in Sham group, and its abundance statistically decreased in the BDL-Yaq-001 group than in the BDL group. The other six families in the heatmap were with marked fold changes between BDL vs Sham, and between BDL-Yaq-001 vs BDL groups (|log2FC|>2). Of these, five were more abundant in the BDL group than in the Sham group. The abundance largely decreased in the Yaq-001-treated group. In addition, to these, one family was less abundant in the BDL group than in the Sham group. The abundance increased in the Yaq-001-treated group. (B) Heatmap of gut microbiome at the Genus level. The Genus Barnesiella with asterisk was statistically differently abundant between BDL vs Sham, and between BDL-Yaq-001 vs BDL groups (Wilcoxon rank sum test, p<0.05). The abundance of this genus was statistically higher in BDL group than in the Sham group, and its abundance statistically decreased in the BDL-Yaq-001 group. The other 19 genera in the heatmap represent those with significant fold change values between BDL vs Sham, and between BDL-Yaq-001 vs BDL groups (|log2FC|>2). Of these, 14 were more abundant in the BDL group compared with the Sham group. The abundance decreased in the Yaq-001-reated BDL group. In addition, five genera were less abundant in the BDL group than in the Sham group. Their abundance increased in the Yaq-001-treated BDL animals. (C, D) Correlation plots between markedly changed genes and gut microbiome at family/genus. The genes were from among the top 20 changed genes in BDL animals with Yaq-001 treatment. Nodes represent either genes (lower semi-circular part) or bacteria (upper semicircular part) at the family and genus level. The nodes are coloured based on the log-fold change for the differential gene expression and differences in the bacterial abundance. The red nodes indicate an increase and blue nodes indicate a decrease. Edges represent the correlation coefficient calculated between genes and microbial genus or family with red indicating a positive correlation and blue a negative correlation. Correlation coefficients greater or equal to 0.4 were plotted in plot C (Spearman’s coefficient≥0.4), and D shows all correlations. *p<0.05. BDL, bile duct ligation.

To further investigate the potential importance of the changes in the microbiome induced by Yaq-001, we correlated these with all significantly changed DEGs and the top 20 DEGs in the four organs. Circos plots indicated a significant correlation between them ( figure 3C,D and online supplemental figure S11A–C ). Porphyromonadaceae was observed to positively correlate with three DEGs—TGFB2 and CASP1 in liver tissue, and FOS in colonic tissue. Also, it correlated negatively with five DEGs—TGFB2, IL-18 and CCR5 in brain tissue, CXCL10 in colon tissue and CCL24 in kidney tissue.

Effect of Yaq-001 on metabolomic profile

Significant difference in acetate/creatinine, glycine/creatinine, lactate/creatinine, betaine/creatinine, trimethylamine oxide/creatinine and bile acid/creatinine ratio were observed in BDL compared with Sham. Treatment of BDL rats with Yaq-001 resulted in significant resolution of acetate/creatinine, glycine/creatinine and lactate/creatinine compared with the untreated BDL animals ( online supplemental figure S12 ).

Studies in CCl4 mice

Effect of yaq-001 on liver injury and fibrosis.

CCl4 mice models (6 weeks and 12 weeks) were used to further confirm the effect of Yaq-001 on liver injury and fibrosis in models of cirrhosis ( figure 4A,B ). Yaq-001 was associated with a significantly lower plasma ALT (p<0.0001, p<0.0001) in both 6-week and 12-week CCl4 models. ALP and TBIL were reduced by Yaq-001 in 6-week CCl4 mice (p=0.040, p=0.001) ( figure 4A,B ). CPA was significantly higher in both CCl4 mice compared with control animals (p=0.0001, p=0.0001), which were significantly reduced with Yaq-001 (p=0.024, p=0.012) ( figure 4A,B ). TUNEL assay showed significantly more intense staining in the liver tissue of CCl4 compared with control mice (p<0.001, p<0.001), which were significantly reduced in Yaq-001-treated CCl4 mice compared with untreated-CCl4 mice (p=0.021, p=0.017) ( figure 4A,B ).

Effect of Yaq-001 on organ dysfunction, ammonia and endotoxaemia in CCl4 mice. (A) Mice underwent CCl4 injection for 6 weeks as a model of cirrhosis (n=6–12/group) and the treatment groups received Yaq-001 for 6 weeks before sacrifice. Plasma ALT, ALP and TBIL concentrations in control (n=6), control-Yaq-001 (n=6), 6-week CCl4 (n=12) and 6-week CCl4-Yaq-001 (n=12) groups. Significantly higher ALT, ALP and TBIL were observed in CCl4 compared with controls (p=0.0001, p=0.0007, p=0.012). Yaq-001-treated CCl4 mice had a significantly lower ALT compared with untreated-CCl4 mice (p<0.0001, p=0.040, p=0.001). H&E and PSR staining of liver tissue. CCl4 mice were associated with a significant increase in collagen proportionate area (CPA) compared with controls (p=0.0001). Yaq-001 had significant effect on CPA in CCl4-Yaq-001 compared with CCl4 mice(p=0.024). TUNEL staining liver tissues. Significantly greater staining was observed in CCl4 compared with controls (p=0.0001). Yaq-001-treated CCl4 mice had a significantly lower TUNEL staining compared with untreated-CCl4 (p=0.021) with Yaq-001 treatment. Venous ammonia concentrations and serum creatinine levels in control (n=6), control-Yaq-001 (n=6), 6-week CCl4 (n=12) and 6-week CCl4-Yaq-001 groups (n=12). Significantly increased ammonia concentrations were observed in CCl4 compared with controls (p=0.0020). Yaq-001 significantly decreased venous ammonia concentrations and serum creatinine levels in CCl4 mice (p=0.025, p=0.005). Endotoxin concentrations in control (n=3), control-Yaq-001 (n=3), 6-week CCl4 (n=10) and 6-week CCl4-Yaq-001 groups(n=10). Significantly higher endotoxin was observed in CCl4 mice compared with control mice (p=0.007). Yaq-001 administration was associated with a significant reduction of venous endotoxin compared with untreated-CCl4 mice (p=0.007). (B) Mice underwent CCl4 injection for 12 weeks as a model of cirrhosis (n=6–12/group) and the treatment groups received Yaq-001 for 6 weeks before sacrifice. Plasma ALT, ALP and TBIL concentrations in control (n=6), control-Yaq-001 (n=6), 12-week CCl4 (n=12) and 12-week CCl4-Yaq-001 (n=12) groups. Significantly higher ALT, ALP and TBIL were observed in CCl4 compared with controls (p=0.0001, p=0.0008, p=0.007). Yaq-001-treated CCl4 mice had a significantly lower ALT compared with untreated-CCl4 mice (p<0.0001). H&E and PSR staining of liver tissue in CCl4 mice. CCl4 mice were associated with a significant increase in collagen proportionate area (CPA) compared with controls (p=0.0001). Yaq-001 had significant effect on CPA in CCl4-Yaq-001 compared with CCl4 mice(p=0.012). TUNEL staining of liver tissues. Significantly higher TUNEL staining was observed in CCl4 compared with controls (p=0.0001). Yaq-001-treated CCl4 mice had a significantly lower TUNEL staining compared with untreated-CCl4 (p=0.017) indicative of a reduction in liver cell death with Yaq-001 treatment. Venous ammonia. Significantly increased ammonia concentrations were observed in CCl4 compared with controls (p=0.001). Yaq-001 significantly decreased venous ammonia concentrations in CCl4 mice (p=0.035). Serum creatinine: Yaq-001 significantly decreased serum creatinine levels in CCl4 mice (p=0.003). Endotoxin concentrations in control (n=3), Control-Yaq-001 (n=3), 12-week CCl4 (n=10) and 12-week CCl4-Yaq-001 groups(n=10). Significantly higher venous endotoxin was observed in CCl4 mice compared with control mice (p=0.007). Yaq-001 administration was associated with a significant reduction of venous endotoxin compared with untreated-CCl4 mice (p=0.043). *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001. ALT, alanine aminotransferase; ALP, alkaline phosphatase; PSR, picrosirius red; TBIL, total bilirubin.

Effect of Yaq-001 on ammonia, organ dysfunction and endotoxaemia

Ammonia: Ammonia concentrations were significantly increased in the 6-week and 12-week CCl4 mice compared with controls (p=0.002, p=0.001), which were significantly reduced by Yaq-001 (p=0.025, p=0.035) ( figure 4A,B ). None of the animals showed signs of overt hepatic encephalopathy.

Kidneys: Higher plasma creatinine was significantly reduced by Yaq-001 treatment (p=0.005, p=0.003) in 6-week and 12-week CCl4 animals ( figure 4A,B ).

Endotoxaemia: Both 6-week and 12-week CCl4 mice exhibited marked endotoxaemia compared with controls (p=0.007, p=0.007), which were significantly reduced with Yaq-001(p=0.007, p=0.043) ( figure 4A,B ).

In vitro studies in intestinal organoids to assess gut permeability

Intestinal organoids were successfully derived and cultured from small intestine of C57BL/6 mice. Intestinal organoids underwent eversion into apical-out polarity in the first 12 hours of suspension culture and collected for identification and subsequent experiments ( figure 5A ). Immunostaining of the microvilli (mv; F-actin) demonstrated that intestinal organoids in suspension had reversed polarity such that the apical surface faced outward ( figure 5A ). Apical-out intestinal organoids possessed goblet cells, which were identified with MUC2 staining ( figure 5B ). Gut permeability of apical-out intestinal organoids was significantly increased by coculturing with faecal water from CCl4 group compared with the control group (p=0.003) ( figure 5C,D ). The gut permeability was significantly decreased with faecal water from Yaq-001 treated CCl4 animals compared with the CCl4 group (p=0.001) ( figure 5C,D ).

Effect of Yaq-001 on gut permeability in intestinal organoids. (A) Intestinal organoids derived and cultured from small intestine of C57BL/6 mice underwent eversion into apical-out polarity in the first 12 hours of suspension culture. Immunostaining of the microvilli (mv; F-actin) demonstrated that intestinal organoids in suspension have reversed polarity from basolateral-out to apical-out. (B) Apical-out intestinal organoids in suspension culture generate goblet cells (MUC2). (C) Gut permeability of apical-out intestinal organoids was significantly increased by coculturing with faecal water from CCl4 group than control group (p=0.003). Gut permeability was notably decreased in faecal water from CCl4-Yaq-001 group compared with CCl4 group (p=0.001). (D) Quantification of the integrated density/area of each group. **p<0.01.

The data regarding safety and tolerability are reported here. Other secondary and exploratory endpoints will be described elsewhere.

Patient characteristics

34 patients were screened for this study at 8-European centres. 28 patients met the study entry criteria and were randomised to either active or placebo groups. Six patients screened did not meet the study entry criteria. Dosing was not initiated in two patients randomised to placebo due to withdrawal of consent ( online supplemental figure S3 , CONSORT). Three patients were included for the second dosing cohort of 8 g. This part of the study was terminated prematurely due to the coronavirus pandemic with none of the patients completing the study duration (data are not included).

In accordance with study entry criteria, all patients had cirrhosis with diuretic-responsive ascites and Child-Pugh score of 7–8. The baseline demographics were similar across treatment groups. The ratio of male to female patients was reflective of the disease state. Compliance in the active and placebo groups was 92.9% and 66.7%, respectively ( table 1 ).

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Safety and tolerability

Of the 14 patients enrolled in the Yaq-001 treatment group, 13 (93%) completed 12 weeks of therapy. The median duration of exposure was 83 (6–94) days. 10 of the 12 (83%) patients who received placebo completed the treatment. The median duration of exposure was 83 (14–86) days. No deaths or serious adverse events were reported in the study. The difference in treatment-emergent adverse events (TEAEs) in patients treated with Yaq-001 and those treated with placebo is presented in table 2 . The most frequently reported TEAEs were gastrointestinal in nature in both the active and placebo groups. Of these, only constipation and diarrhoea were evaluated by the clinical investigator as possibly related to the investigational product. One placebo-treated patient withdrew from the study due to diarrhoea.

Adverse and serious events

Across both treatment groups, 40/51 (78%) of the reported TEAEs were evaluated by the clinical investigator as not related or unlikely related (32/38; 84% for the active treatment group; 8/13; 62% for the placebo group). The incidence of adverse events reported was reflective of the targeted subject population for this clinical investigation. The majority of the TEAEs reported were not considered by the clinical investigator to be related to treatment and were mild in intensity. Systemic antibiotics were administrated for the following TEAEs in the active arm: amoxicillin—acute bronchitis; clarithromycin—acute bronchitis; phosphomycin—urinary tract infection. None of these infections were related to the administration of the investigational product. Drugs received by the patients at the time of randomisation and during follow-up are listed in online supplemental tables S5 and S6 . Treatment-emergent, clinically significant laboratory abnormalities are listed in table 3 . None were deemed treatment related by the investigator.

Safety parameters: clinical laboratory assessments, royal free global assessment and micronutrient concentrations

Clinical, haematological and biochemical variables

The data are summarised in table 3 . No significant changes in any of the clinical parameters were observed in any of the groups. Although there was a trend towards a reduction in the white cell count and C reactive protein in the Yaq-001 group, the differences were not statistically significant.

Nutritional status

The data are summarised in table 3 . No significant differences were observed in either treatment group with regard to global nutritional status, vitamin B 12 and folate, vitamin A or E, or copper zinc, and selenium. Median vitamin A, zinc and baseline vitamin D concentrations were below the limit of normal range but no differences between treatment groups were observed. No changes were observed in any of the micronutrient parameters with treatment and these were evenly matched between groups. Any baseline abnormalities were attributable to the underlying cirrhosis.

The results of the study showed that Yaq-001 prevented progression of liver injury and fibrosis in animal models of cirrhosis and significantly reduced the mortality of ACLF animals. This effect of Yaq-001 on ACLF mortality will need to be confirmed in patients. This was associated with positive impact on markers of gut permeability, liver injury, portal pressure, brain and kidney dysfunction. These pleiotropic effects of Yaq-001 were associated with partial restoration of the composition of the microbiome bacterial community, reduction in the severity of endotoxaemia, ammonia, inflammation, cell death, signalling pathways and LPS sensitivity. A phase 2 equivalent, multicentre, double-blind, randomised, placebo-controlled clinical trial in patients with cirrhosis confirmed regulatory compliance and, safety and tolerability of Yaq-001, thereby, providing evidence of clinical translatability. The data provide the rationale to proceed to further clinical trials.

Translocation of bacteria, its products and metabolites are critically important in the progression of hepatic fibrosis and pathogenesis of complications of cirrhosis. 1 17–20 Indeed, selective gut decontamination using norfloxacin or rifaximin is the current standard of care for secondary prophylaxis of patients with spontaneous bacterial peritonitis and hepatic encephalopathy, respectively. 21 22 However, the use of these antibiotic strategies is limited to patients with advanced cirrhosis and induces the risk of antibiotic resistance. 23 The data presented here provide a safe, gut-restricted, non-antibiotic strategy, Yaq-001, which has the potential to diminish translocation and prevent the progression of hepatic injury, fibrosis and prevent extrahepatic organ injury in models of cirrhosis. The in vitro studies demonstrate that Yaq-001 has the optimal pore size distribution to bind intraluminal factors such as free endotoxin. We also tested in vitro bacterial growth kinetics of two species, which were not affected by Yaq-001, an observation that was subsequently confirmed in the studies in the BDL animal model where no change diversity was observed.

Endotoxaemia has been implicated in immune dysfunction resulting in a dysregulated systemic inflammatory response, which is strongly associated with the progression of fibrosis, cirrhosis and occurrence of ACLF. 24 25 Yaq-001 reduced the severity of endotoxaemia and bacterial DNA positivity, which was associated with attenuated systemic inflammation. Significant improvements in LPS-induced ROS production were observed in trafficking portal venous monocytes suggesting that Yaq-001 had attenuated the primed state of monocyte/macrophage populations within the gut–liver axis. This observed reduction in LPS-induced ROS production may be important in explaining the reduction in plasma IL-1β in LPS-treated BDL rats.

Plasma D-lactate, a marker of increased gut permeability was reduced in the Yaq-001 treated BDL rats. 26 Elevated plasma D-lactate levels in cirrhosis are associated with decompensation. 22 Transcriptomic analysis of colonic tissue demonstrated upregulation of genes associated with necroptosis, apoptosis and inflammation in BDL animals. Functional analyses pointed to the modulation of colonic inflammation by Yaq-001, IL-17 signalling, which is known to have diverse biological functions, promoting protective immunity against many pathogens, neutrophil recruitment, antimicrobial peptide production and enhanced barrier function. 27 28 To further validate the potential effect of Yaq-001 in modulating gut permeability, we performed experiments in intestinal organoids that were incubated with faecal water. 29 The data confirmed that even in in vitro settings, faecal water obtained from the faeces of CCl4-induced cirrhosis animals enhanced permeability of the organoids, which was prevented in the faecal water obtained from animals that were treated with Yaq-001. The data support the hypothesis that Yaq-001 impacts on the factors in the gut responsible for increasing gut permeability in cirrhosis.

Yaq-001 significantly reduced the severity of liver injury and portal hypertension in both the BDL and BDL-LPS models of cirrhosis and ACLF. The lack of significant differences in CPA between untreated and Yaq-001-treated BDL groups suggests that the reduction in portal pressure is possibly due to modulation of the dynamic component of portal hypertension, in which inflammation is known to play a role and proposes Yaq-001 as a potential treatment for portal hypertension. 30 31 Reduction in ALT levels and TUNEL staining confirmed a reduction in liver injury in the Yaq-001 treated animals. The reduction in liver injury in the LPS treated BDL animals suggests that Yaq-001 has a particular effect on endotoxin sensitivity in vivo . This hypothesis was tested in isolated Kupffer cells, which confirmed that LPS-induced ROS production was significantly impacted by Yaq-001 treatment.

Transcriptomic analysis of liver tissue demonstrated that the upregulated genes, CXCL16, CASP1 and TGFB2 in BDL rats was prevented by Yaq-001 administration. Silencing of CXCL16 alleviates hepatic ischaemia reperfusion injury and CXCL16 variant is also associated with hepatitis B virus-related acute liver failure. 32 CASP1 mediates proinflammatory cytokine release and pyroptotic cell death in cirrhosis and its inhibition has been shown to prevent ACLF. 33 TGFB2 is an important mediator of cellular senescence. 34 35 Of note, Yaq-001 also modified necroptosis and cytosolic DNA-sensing pathways representing cell death, which are known to be activated by LPS and can trigger systemic inflammation. 36 These effects of Yaq-001 potentially explain the effect of Yaq-001 in reducing liver injury. 33 37

Yaq-001 administration had a significant impact on time to coma of ACLF rats, which is considered a surrogate for mortality compared with untreated controls. Whether it impacts truly on mortality of ACLF animals will require more confirmation. Yaq-001 also significantly lowered portal venous and arterial ammonia levels, which was associated with reduced brain water. Transcriptomic analysis of brain tissue showed that IL-18, TGFB2, CCR5 and IL-23A were dysregulated in BDL rats and these were corrected by Yaq-001. IL-18 is released during pyroptosis by activation of the inflammasome complex in neuroinflammatory and neurodegenerative diseases. 38 The effect of Yaq-001 on TGFB2 may mean that it has an impact on cellular senescence, which is known to be associated with hepatic encephalopathy. CCR5 has been implicated in neuroprotection and is a novel therapeutic target in stroke. 39 The impact of Yaq-001 on IL-23A indicates possible reduction in neuroinflammation.

In both cirrhosis and ACLF models, Yaq-001 reduced renal dysfunction. Transcriptomic analysis of kidney tissue showed that CCL24 was downregulated in BDL rats, which was prevented in the Yaq-001-treated animals. CCl4 protects renal function in the development of early diabetic nephropathy by exerting an anti-inflammatory effect. 40 Yaq-001 impacted, on the cytokine-cytokine receptor interactions and chemokine and toll-like signalling pathways, which were abnormal in the BDL rats.

BDL animals become sarcopenic and lose weight, which were significantly abrogated by Yaq-001. 41 The possible mechanisms underlying this effect are likely multifactorial. 42 Yaq-001 reduced ammonia significantly, which has been shown to induce sarcopenia. 43 Weight loss in cirrhosis is also attributed to increased catabolic state in the context of systemic inflammatory response and thus the observed improvement in body weight may reflect the diminished catabolic state with reduced inflammation. 42

The clinical effects of Yaq-001 observed in the BDL models were validated in the CCl4-induced liver injury animal models. Two models were studied. In the first (6-week model), Yaq-001 was administered in a preventative mode starting its administration with the onset of liver injury during administration of CCl4. The results showed significant reduction in the severity of liver injury, fibrosis and progression to cirrhosis, endotoxaemia, creatinine and ammonia levels. In the second (12-week model), Yaq-001 was administered starting at 6 weeks when the animal already had advanced fibrosis/cirrhosis. Again, significant reduction in markers of liver injury, fibrosis, endotoxaemia, creatinine and ammonia were observed. Extrapolating these observations to humans, the results from the 6-week model suggest that Yaq-001 may be useful to prevent the progression of fibrosis in patients without cirrhosis and, from the 12-week model, the possibility of prevention of progression of liver disease in those with well-compensated cirrhosis.

Gut microbiota are important in modulating intestinal health, permeability, bacterial translocation, systemic inflammation and complications of cirrhosis. 44–46 BDL was associated with marked changes in the abundance of microbiota, which were reversed by Yaq-001. In particular, the abundance of Porphyromonadaceae and Barnesiella were significantly elevated in BDL rats and significantly decreased with Yaq-001. This change is potentially important as Porphyromonadaceae is a proinflammatory bacterium that has been positively correlated with hepatic encephalopathy and, Barnesiella and Porphyromonadaceae have been associated with liver cancer. 47–49 Urinary nuclear magnetic resonance (NMR) analysis reflects the combined metabolic status of both host and microbiota. Yaq-001 was associated with a distinct shift of acetate, glycine and lactate in metabolomic profile in BDL rats. These metabolites are generated by mixed acid fermentation (MAF), typically by bacteria such as Enterobacter. MAF is not the preferred metabolic pathway for facultative anaerobes and may be indicative that Enterobacter populations are under conditions of metabolic stress in Yaq-001 treated BDL animals. As these species are often pathogenic in cirrhosis, this may represent a beneficial change. However, the exact mechanisms by which the change in the microbiome results in improvement in distant organ function and gene expression cannot be directly inferred from the data derived from this study. One possibility is that alongside LPS adsorption and modulation of other unmeasured toxins, the milieu of the gut is changed allowing proliferation of more autochthonous bacteria, which impacts on gut inflammation and reduces gut permeability. 46 This hypothesis is supported by the organoid experiments. Reduction in permeability would result in a reduction in endotoxaemia, systemic inflammation, improvement of organ function and LPS-sensitivity. In this study, most of these changes have been described individually but whether this is happening in sequence has not been investigated.

As Yaq-001 is completely excreted unchanged in the stool, it is regulated in Europe as a device. Therefore, the clinical trial was performed both according to ISO standards and ICH-GCP guidance. The results of this first-in-man, multicentre, double-blind, randomised, placebo-controlled clinical trial suggested that oral Yaq-001 at a dose of 4 g nocte was well tolerated with a favourable safety profile. Despite the rapid adsorption kinetics for bacterial toxins and metabolites, Yaq-001 treatment had no negative impact on micronutrient levels or on nutritional profile as assessed by the gold standard Royal Free Global Assessment tool. These data must be interpreted keeping in mind that Yaq-001 was administered postprandially, separated from drugs by 4 hours as necessitated by the protocol. It is important to note that the studies were performed in stable cirrhosis patients, many of whom had minimal evidence of systemic inflammation and therefore, any clinical effect of this intervention was difficult to gauge. However, future analysis of the available samples from the blood and stool will provide answers as to whether Yaq-001 modulates the gut microbiome, inflammation and endotoxaemia.

These results must be considered in view of some limitations. First, the rodent microbiome is not directly analogous to the human and further clinical studies will be required to verify the effects on the gut microbiome’s bacterial composition. Second, although Yaq-001 was effective in adsorbing a variety of bile acids in vitro and reduced bile acids significantly in Sham animals, no impact on bile acids was seen in BDL animals. This possibly reflects the effect of the BDL model, where no increase in bile acids was observed. Also, no changes in bile acids were observed in CCl4 animals but these animals did not have elevated bile acid either. Further studies on effect of Yaq-001 bile acids both in the circulation and stool need to be performed to confirm safety. Third, although, Yaq-001 was observed to impact positively on the gene expression profiles of multiple pathways, their exact relevance at the protein or cellular level has not been explored. Additionally, the limited genes in the different organs assessed in this study are a potential source of bias as they focused on pathways likely to be impacted by Yaq-001. Thus, further studies using unbiased approaches should be performed to define the true effect of Yaq-001. Fourth, although survival benefit was observed with prior Yaq-001 administration in the ACLF model, further studies are needed to confirm this finding. Fifth, as only one dose of Yaq-001 was tested in the clinical trial, further dose-ranging studies will be needed to define optimal dosing for safety and efficacy. However, the animal toxicity studies that were performed by an independent laboratory for regulatory purposes, showed evidence of safety in much larger doses than that administered in the present studies (summary in online supplemental file ). Finally, although Yaq-001 was safe and tolerable, further analyses are needed to clarify its clinical effects in patients.

In conclusion, the data provide compelling evidence for the potential of Yaq-001 as a novel gut-restricted adsorbent targeting endotoxin and ammonia that impacts on the gut microbiome, gut permeability, systemic inflammation, liver injury and fibrosis and, organ function in models of cirrhosis and improves survival in ACLF. The placebo-controlled clinical trial of Yaq-001 in cirrhosis patients provides evidence of safety and tolerability allowing translation to the next phase of clinical studies to define its potential as a novel therapeutic for patients with cirrhosis.

Ethics statements

Patient consent for publication.

Not applicable.

Ethics approval

This study involves human participants and was approved by UK: South West—Exeter Research Ethics Committee; Ref No. 17/SW/0144France: Le Comité de Protection des Personnes Sud Méditerranée II, agréé par arrêté: Ref No. 17/SW/0144Portugal: Assunto: Estudo Clinico com Intervenao de Dispositivo Medico com o Protocolo n2 Yaq001-S- 001 e Codigo CEIC 1712GK893. Participants gave informed consent to participate in the study before taking part.

Acknowledgments

We would like to thank Fraser Simpson (Department of Genetics, Evolution and Environment, University College London) for his support to perform the Nanostring. The urinary NMR studies were facilitated by a Medical Research Council research grant under the High-throughput 'omic' Science and Imaging funding scheme (MC_PC_13045). University of Brighton coauthors acknowledge Prof Sergey Mikhalovsky and Dr Carol Howell in discussion and research leading to the CARBALIVE grant. The authors would like to thank all the patients and public who provided input into designing the study and those that took part in the study.

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Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

• Data supplement 1
• Data supplement 2
• Data supplement 3
• Data supplement 4

JL and JM are joint first authors.

X @Zac_MD, @DrLAEdwards, @Ijcox_nmr, @drgautammehta

JL and JM contributed equally.

Deceased Dr Soeda is deceased

Correction notice This article has been corrected since it published Online First. Figure 4A has been replaced.

Contributors JL: performed CCl4 animal experiments; data acquisition and analysis; intestinal organoid experiments; paper organisation, drafting and writing; JMacNaughtan and RJ: concept; study design; performed animal experiments; data acquisition and analysis; clinical trial lead; paper organisation, drafting and writing; AJCK, JMG, CJ, GZ, KH, MARG, PG, ES, HC-P, FD, PCordero, VV, GM and DG: Clinical trial; TP and YJ: Analysis of the microbiome data and correlation analyses; FC and SS: analysis of the microbiome data, correlation analyses and transcriptomics analyses; AH: performed all the bile duct ligation animal studies; sample analyses; HJ, QJ and HW: performed CCl4 animal experiments; data acquisition and analysis; AP: BDL animal experiments; data acquisition; FDC: BDL animal experiments; data acquisition and analysis; GI: BDL animal experiments; data acquisition and analysis; PCaraceni and JS: data acquisition and cell studies; LM, TA, MK and DG: Yaq-001 characterisation and manufacture; JO: concept; study design; data acquisition and cell studies; KC: regulatory and clinical trial design; JVL: analysis of metabolomics data; AJ: data acquisition and analysis; data organisation; SE: analysis of metabolic effects of Yaq-00; CM: clinical trial; study design; AG: data acquisition and analysis biobanking; LAE: data acquisition and analysis; IJC: analysis of metabolic effects of Yaq-001; RW and VA: clinical trial; study design; RE, JV and MP: statistics; ND: concept; study design; performed animal experiments; data acquisition and analysis; RM: concept; study design; paper organisation, drafting and writing; SSandeman: concept; study design; in vitro studies of Yaq-001; SShoaie: analysis of the microbiome data, correlation analyses and transcriptomics analyses; JMarchesi: microbiome sequencing and analysis of the microbiome data; AA: clinical trial and trial design; FA: concept; study design; data acquisition and analysis. RJ accepts full responsibility for the work presented in this paper. the conduct of the study, has access to all the data and controlled the decision to publish the study.

Funding This study was performed with support from a grant from the EU H2020, Grant Agreement number: 634579—CARBALIVE—H2020-PHC-2014-2015/H2020-PHC-2014 programme. JMarchesi and the Division of Digestive Diseases at Imperial College London receives financial support from the NIHR Imperial Biomedical Research Centre.

Competing interests JMacNaughtan: Shareholder in Yaqrit—no payments received; LM: Yaqrit Employee; KC: Yaqrit consultant; CM: Full-time employee of Yaqrit—salary, Share options in Yaqrit Discovery—no payment received; TA: Full-time employee of Yaqrit—Salary; MK: Full-time employee of Yaqrit—salary, Shares and Share options in Yaqrit Discovery—no payment received; DG: Share options—Yaqrit; AG: Shareholder—Yaqrit; RPM: Shareholder in Yaqrit —No payments received; SShoaie: Co-founder of Gigabiome, Bash Biotech and DAS Microbiome; JMarchesi: JMarchesi has received consultancy fees from EnteroBiotix and Cultech, and speaker fees from Falk Forum; RJ: RJ is the inventor of OPA, which has been patented by UCL and licensed to Mallinckrodt Pharma. He is also the founder of Yaqrit Discovery, Hepyx (spin out companies from University College London), and Cyberliver. He has research collaborations with Yaqrit Discovery. Yaq-001 was licensed by Yaqrit from UCL.

Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

In the PDF this Figure is extremely squashed. It meeds to be on a full page or even 2 pages to allow full visibility

This Figure is very squashed in the PDF I saw. Should be expanded to a full page or even 2 pages please to allow readability

Once these have been corrected, please share the revised version with me to recheck please.

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Computer Science > Robotics

Title: a new taxonomy for automated driving: structuring applications based on their operational design domain, level of automation and automation readiness.

Abstract: The aim of this paper is to investigate the relationship between operational design domains (ODD), automated driving SAE Levels, and Technology Readiness Level (TRL). The first highly automated vehicles, like robotaxis, are in commercial use, and the first vehicles with highway pilot systems have been delivered to private customers. It has emerged as a crucial issue that these automated driving systems differ significantly in their ODD and in their technical maturity. Consequently, any approach to compare these systems is difficult and requires a deep dive into defined ODDs, specifications, and technologies used. Therefore, this paper challenges current state-of-the-art taxonomies and develops a new and integrated taxonomy that can structure automated vehicle systems more efficiently. We use the well-known SAE Levels 0-5 as the "level of responsibility", and link and describe the ODD at an intermediate level of abstraction. Finally, a new maturity model is explicitly proposed to improve the comparability of automated vehicles and driving functions. This method is then used to analyze today's existing automated vehicle applications, which are structured into the new taxonomy and rated by the new maturity levels. Our results indicate that this new taxonomy and maturity level model will help to differentiate automated vehicle systems in discussions more clearly and to discover white fields more systematically and upfront, e.g. for research but also for regulatory purposes.

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