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Background Liver transplantation (LT) activities during the COVID-19 pandemic have been curtailed in many countries. The impact of various policies restricting LT on outcomes of potential LT candidates is unclear. Methods We studied all patients on the nationwide LT waitlists in Hong Kong and Singapore between January 2016 and May 2020. We used continuous time Markov chains to model the effects of different scenarios and varying durations of disruption on LT candidates. Findings With complete cessation of LT, the projected 1-year overall survival (OS) decreased by 3•6%, 10•51% and 19•21% for a 1-, 3- and 6-month disruption respectively versus no limitation to LT, while 2-year OS decreased by 4•1%, 12•55%, and 23•43% respectively. When only urgent (acute-on-chronic liver failure [ACLF] or acute liver failure) LT was allowed, the projected 1-year OS decreased by a similar proportion: 3•1%, 8•41% and 15•20% respectively. When deceased donor LT (DDLT) and urgent living donor LT (LDLT) were allowed, 1-year projected OS decreased by 1•2%, 5•1% and 8•85% for a 1-, 3- and 6-month disruption respectively. OS was similar when only DDLT was allowed. Complete cessation of LT activities for 3-months resulted in an increased projected incidence of ACLF and hepatocellular carcinoma (HCC) dropout at 1-year by 49•1% and 107•96% respectively. When only urgent LT was allowed, HCC dropout and ACLF incidence were comparable to the rates seen in the scenario of complete LT cessation. Interpretation A short and wide-ranging disruption to LT results in better outcomes compared with a longer duration of partial restrictions. Funding None to disclose.

1The habenula is an evolutionarily conserved structure of the vertebrate brain that is essential for behavioural flexibility 2 and mood control. It is spontaneously active and is able to access diverse states when the animal is exposed to sensory 3 stimuli or reward. Here we analyze two-photon calcium imaging time-series of the habenula of larval zebrafish and find 4 that percolation occurs, indicating the presence of long-range spatial correlations within each side of the habenula, with 5 percolation occurring independently in each side. On the other hand, the analysis of neuronal avalanches suggests that the 6 system is subcritical, implying that the flexibility in its dynamics may result from other dynamical processes. 7 130[36]. 131Upon analyzing the pairwise correlation function for the four datasets we observe two distinct behaviors for the power 132 law regime. We saw that the four datasets can be divided into two groups with distinct power law exponents. We note that 133 this may potentially reflect differences in mode of activity of the habenula, or simply be a variation due to the fish itself, 134 which we are unable to determine at this point in time. Nevertheless, the scale invariant behavior of the function suggests 135 long-range spatial correlations among the neurons in the habenula. More importantly, the scale invariant regime extends 136 only up to the scale of any one side of the habenula, which suggests that percolation occurs independently in each side. 137The presence of long-range spatial correlation suggests that the temporal aspect may display critical behavior as well. 138Despite so, our analysis suggests that the habenula are subcritical, i.e. the spatiotemporal neuronal dynamics are less active 139 than the critical state. 140In the absence of criticality, then, how could the habenula achieve its flexibility in terms of accessing different modes 141 of activity? Two possibilities come to mind; the first of which is that the habenula operates not at, but near criticality, as 142 has been suggested in literature [39]. Being near criticality may also explain why we observe the other telltale signs of 143 criticality (including percolation), while failing only the more stringent properties (such as the scaling relation). 144Another possibility lies in our fundamental assumption, which is that only adjacent cells are taken to be connected. 145While it is known that gap junction (which mediates communication among adjacent neurons) are present in habenula 146 7 neurons [40], it could be the case that long-range connections play an important role in the development and transmission 147 of avalanches, i.e. the habenula is actually critical, but we perceive it to be otherwise due to the omission of long-range 148 connections. In such a situation, one large (and long-lasting) avalanche would be perceived as multiple smaller (and 149 potentially shorter) avalanches, causing the probability mass in both distributions to bias towards the left side. Hence, it 150 could explain the sub-power law regim...

The habenula is an evolutionarily conserved structure of the vertebrate brain that is essential for behavioural flexibility and mood control. It is spontaneously active and is able to access diverse states when the animal is exposed to sensory stimuli.Here we investigate the dynamics of habenula spontaneous activity, to gain insight into how sensitivity is optimized. Twophoton calcium imaging was performed in resting zebrafish larvae at single cell resolution. An analysis of avalanches of inferred spikes suggests that the habenula is subcritical. Activity had low covariance and a small mean, arguing against dynamic criticality. A multiple regression estimator of autocorrelation time suggests that the habenula is neither fully asynchronous nor perfectly critical, but is reverberating. This pattern of dynamics may enable integration of information and high flexibility in the tuning of network properties, thus providing a potential mechanism for the optimal responses to a changing environment. Significance StatementSpontaneous activity in neurons shapes the response to stimuli. One structure with a high level of spontaneous neuronal activity is the habenula, a regulator of broadly acting neuromodulators involved in mood and learning. How does this activity influence habenula function? We show here that the habenula of a resting animal is near criticality, in a state termed reverberation. This pattern of dynamics is consistent with high sensitivity and flexibility, and may enable the habenula to respond optimally to a wide range of stimuli.

The lateral habenula, a regulator of neuromodulators that is activated by aversive stimuli, contains a molecular clock whose significance is unknown. Here, using zebrafish, we test the hypothesis that the habenula clock affects the switch in internal state that is triggered by an aversive stimulus. Consistent with the expression of clock genes, habenula neural activity varies in a circadian manner. Disruption of clock function, by expression of a truncated clock gene specifically in the habenula, did not affect acute responses to the alarm pheromone Schreckstoff. However, behaviours elicited by transient exposure to Schreckstoff namely freezing in a novel environment and dark avoidance, were reduced. Behaviours that are regulated by the pineal clock and not triggered by stressors were unaffected. These findings establish that the habenula clock independently influences the stress response induced by an aversive stimulus, indicating that this clock underlies circadian variation in response to a stressor.

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Granger causality is a commonly used method for uncovering information flow and dependencies in a time series. Here, we introduce JGC (Jacobian Granger causality), a neural network-based approach to Granger causality using the Jacobian as a measure of variable importance, and propose a variable selection procedure for inferring Granger causal variables with this measure, using criteria of significance and consistency. The resulting approach performs consistently well compared to other approaches in identifying Granger causal variables, the associated time lags, as well as interaction signs. In addition, we also discuss the need for contemporaneous variables in Granger causal modeling as well as how these neural network-based approaches reduce the impact of nonseparability in dynamical systems, a problem where predictive information on a target variable is not unique to its causes, but also contained in the history of the target variable itself.

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