Sudden cardiac arrest in patients with cancer in the general population: insights from the Paris-SDEC registry.

BACKGROUND: Data on the management of patients with cancer presenting with sudden cardiac arrest (SCA) are scarce. We aimed to assess the characteristics and outcomes of SCA according to cancer history. METHODS: Prospective, population-based registry including every out-of-hospital SCA in adults in Paris and its suburbs, between 2011 and 2019, with a specific focus on patients with cancer. RESULTS: Out of 4069 patients who had SCA admitted alive in hospital, 207 (5.1%) had current or past medical history of cancer. Patients with cancer were older (69.2 vs 59.3 years old, p<0.001), more often women (37.2% vs 28.0%, p=0.006) with more frequent underlying cardiovascular disease (41.1% vs 32.5%, p=0.01). SCA happened more often with a non-shockable rhythm (62.6% vs 43.1%, p<0.001) with no significant difference regarding witness presence and cardiopulmonary resuscitation (CPR) performed. Cardiac causes were less frequent among patients with cancer (mostly acute coronary syndromes, 25.5% vs 46.8%, p<0.001) and had more respiratory causes (pulmonary embolism and hypoxaemia in 34.2% vs 10.8%, p<0.001). Still, no difference regarding in-hospital survival was found after SCA in patients with cancer versus other patients (26.2% vs 29.8%, respectively, p=0.27). Public location, CPR by witness and shockable rhythm were independent predictors of in-hospital survival after SCA in the cancer group. CONCLUSIONS: One in 20 SCA occurs in patients with a history of cancer, yet with fewer cardiac causes than in patients who are cancer-free. Still, in-hospital outcomes remain similar even in patients with known cancer. Cancer history should therefore not compromise the initiation of resuscitation in the context of SCA.

Analysis during chest compressions in out-of-hospital cardiac arrest patients, a cross/sectional study: The DEFI 2022 study.

AIMS: During out-of-hospital cardiac arrest (OHCA), an automatic external defibrillator (AED) analyzes the cardiac rhythm every two minutes; however, 80% of refibrillations occur within the first minute post-shock. We have implemented an algorithm for Analyzing cardiac rhythm While performing chest Compression (AWC). When AWC detects a shockable rhythm, it shortens the time between analyses to one minute. We investigated the effect of AWC on cardiopulmonary resuscitation quality. METHOD: In this cross-sectional study, we compared patients treated in 2022 with AWC, to a historical cohort from 2017. Inclusion criteria were OHCA patients with a shockable rhythm at the first analysis. Primary endpoint was the chest compression fraction (CCF). Secondary endpoints were cardiac rhythm evolution and survival, including survival analysis of non-prespecified subgroups. RESULTS: In 2017 and 2022, 355 and 377 OHCAs met the inclusion criteria, from which we analyzed the 285 first consecutive cases in each cohort. CCF increased in 2022 compared to 2017 (77% [72-80] vs 72% [67-76]; P < 0.001) and VF recurrences were shocked more promptly (53 s [32-69] vs 117 s [90-132]). Survival did not differ between 2017 and 2022 (adjusted hazard-ratio 0.96 [95% CI, 0.78-1.18]), but was higher in 2022 within the sub-group of OHCAs that occurred in a public place and within a short time from call to AED switch-on (adjusted hazard ratio 0.85[0.76-0.96]). CONCLUSIONS: OHCA patients treated with AWC had higher CCF, shorter time spent in ventricular fibrillation, but no survival difference, except for OHCA that occurred in public places with short intervention time.

Transcription regulates the spatio-temporal dynamics of genes through micro-compartmentalization.

Although our understanding of the involvement of heterochromatin architectural factors in shaping nuclear organization is improving, there is still ongoing debate regarding the role of active genes in this process. In this study, we utilize publicly-available Micro-C data from mouse embryonic stem cells to investigate the relationship between gene transcription and 3D gene folding. Our analysis uncovers a nonmonotonic - globally positive - correlation between intragenic contact density and Pol II occupancy, independent of cohesin-based loop extrusion. Through the development of a biophysical model integrating the role of transcription dynamics within a polymer model of chromosome organization, we demonstrate that Pol II-mediated attractive interactions with limited valency between transcribed regions yield quantitative predictions consistent with chromosome-conformation-capture and live-imaging experiments. Our work provides compelling evidence that transcriptional activity shapes the 4D genome through Pol II-mediated micro-compartmentalization.

Comparison of mannitol and hypertonic saline solution for the treatment of suspected brain herniation during prehospital management of traumatic brain injury patients.

BACKGROUND AND IMPORTANCE: Occurrence of mydriasis during the prehospital management of traumatic brain injury (TBI) may suggest severe intracranial hypertension (ICH) subsequent to brain herniation. The initiation of hyperosmolar therapy to reduce ICH and brain herniation is recommended. Whether mannitol or hypertonic saline solution (HSS) should be preferred is unknown. OBJECTIVES: The objective of this study is to assess whether HSS, compared with mannitol, is associated with improved survival in adult trauma patients with TBI and mydriasis. DESIGN/SETTING AND PARTICIPANTS: A retrospective observational cohort study using the French Traumabase national registry to compare the ICU mortality of patients receiving either HSS or mannitol. Patients aged 16 years or older with moderate to severe TBI who presented with mydriasis during prehospital management were included. OUTCOME MEASURES AND ANALYSIS: We performed propensity score matching on a priori selected variables [i.e. age, sex and initial Coma Glasgow Scale (GCS)] with a ratio of 1 : 3 to ensure comparability between the two groups. The primary outcome was ICU mortality. The secondary outcomes were regression of pupillary abnormality during prehospital management, pulsatility index and diastolic velocity on transcranial Doppler within 24 h after TBI, early ICU mortality (within 48 h), ICU and hospital length of stay. RESULTS: Of 31 579 patients recorded in the registry between 2011 and 2021, 1417 presented with prehospital mydriasis and were included: 1172 (82.7%) received mannitol and 245 (17.3%) received HSS. After propensity score matching, 720 in the mannitol group matched 240 patients in the HSS group. Median age was 41 years [interquartile ranges (IQR) 26-60], 1058 were men (73%) and median GCS was 4 (IQR 3-6). No significant difference was observed in terms of characteristics and prehospital management between the two groups. ICU mortality was lower in the HSS group (45%) than in the mannitol group (54%) after matching [odds ratio (OR) 0.68 (0.5-0.9), P  = 0.014]. No differences were identified between the groups in terms of secondary outcomes. CONCLUSION: In this propensity-matched observational study, the prehospital osmotherapy with HSS in TBI patients with prehospital mydriasis was associated with a lower ICU mortality compared to osmotherapy with mannitol.

Controlled donation after circulatory death in post-cardiac arrest patients: Estimates from a large registry.

BACKGROUND: Controlled donation after circulatory death (cDCD) in post-anoxic brain injury is a valuable source of organs that is still underused in some countries. We assessed the number of potential cDCD donors after out-of-hospital cardiac arrest (OHCA) in Paris and its suburbs and extrapolated the results to the French population. METHODS: Using the large regional registry of the Great Paris area, we prospectively included all consecutive adults with OHCA with a stable return of spontaneous circulation (ROSC) who ultimately died in the intensive care unit (ICU) after withdrawal of life-sustaining treatments (WLST) due to post anoxic brain injury. The primary endpoint was potential for organ donation by cDCD in this population. The number of potential cDCD donors was calculated and extrapolated to the entire French population. RESULTS: Between 2011 and 2018, 4638 patients with stable ROSC were admitted to ICUs after OHCA, and 3170 died in ICU, of which 1034 died after WLST due to post-anoxic brain injury. When considering French criteria, 421/1034 patients (41%) would have been potential cDCD donors (55 patients per year in a 4.67 million population). After standardization for age and sex, the potential for cDCD was 515 (95% CI 471-560) patients per year in France corresponding to an annual incidence of 1.18 per 100 000 inhabitants per year. CONCLUSIONS: Organ donation by cDCD after cardiac arrest could provide a large pool of donors in France.

Psychological, cognitive, and physiological impact of hazards casualties' trainings on first responders: the example of a chemical and radiological training. An exploratory study.

Background: First responders are among the first to respond to hazards casualties. They might operate in volatile, uncertain, complex, and ambiguous (VUCA) environments. While they have underlined the need to improve their knowledge and training to face these environments, there are few data regarding the stress induced by these trainings. Chemical, biological, radiological, and nuclear (CBRN) hazards casualties' trainings seem to be a good model of "in vivo" stress. First responders must operate in a hostile and encountered environment with a CBRN protective equipment that places demand on their psychological, cognitive, and physiological capacities. Current research recognizes that the activity of the parasympathetic system (PSS) can be used as an objective marker of stress adaptation, measured as heart rate variability (HRV). Objectives: To compare between baseline and simulation the evolution of the parasympathetic activity (primary outcome), anxiety, emotions, cognitive load, and body posture awareness (secondary outcomes). Methods: A total of 28 first responders attended to three simulated scenarios requiring CBRN management of casualties. One day before simulation, we collected HRV data (baseline). The simulations' day (pre-, post-simulation) we collected anxiety score (STAI-Y B), emotions (SPANE), cognitive load (NASA TLX), body posture awareness (PAS) and HRV. The morning after we collected the PAS score (recovery). We compare data' evolution between different times of the simulation. Results: (i) A high level of anxiety at baseline [Median 51 (46; 56)] which decreased between pre- and post-simulation (p = 0.04; F = 2.93); (ii) a post-simulation decrease in negative feelings (p = 0.03); (iii) a decrease in body awareness after simulation which returned to the initial level at recovery (p = 0.03; F = 3.48); (iv) a decrease in mean RR between baseline, pre- and post-simulation (p = 0.009; F = 5.11). There were no significant difference between times on others analysis of HRV. Conclusion: Prior to simulation, participants experienced anticipatory anxiety. Simulations training practiced regularly could be one way to combat anticipatory anxiety.

FIRECARE: An Evidence-Based Prevention Program to Reduce Burnout among Prehospital Caregivers: Benefits of a Combined Mindfulness, Heart Coherence Training, and Positive Psychology Intervention.

BACKGROUND: Burnout among emergency health care professionals is well-described, especially during the COVID-19 pandemic. Prevention interventions, such as mindfulness, focus on the management of stress. OBJECTIVE: To evaluate the effects of the FIRECARE program (a mindfulness intervention, supplemented by heart coherence training and positive psychology workshops) on burnout, secondary stress, compassion fatigue, and mindfulness among advanced life support ambulance staff of the Paris Fire Brigade. MATERIALS AND METHODS: We used a non-randomized, two-group quasi-experimental study design with a waitlist control and before-and-after measurements in each group. The intervention consisted of six, once-weekly, 2.5-h sessions that included individual daily meditation and cardiac coherence practice. The study compared intervention and waitlist control groups, and investigated baseline, post-program, and 3-month follow-up change on burnout (measuring using the ProQOL-5 scale) and mindfulness (measuring using the FMI scores). Baseline burnout (measured using the ProQOL-5) was evaluated and used in the analysis. RESULTS: Seventy-four 74 participants volunteered to participate; 66 were included in the final analysis. Of these, 60% were classified as suffering from moderate burnout, the 'burnout cluster'. A comparison of intervention and waitlist control groups found a decrease in the burnout score in the burnout cluster (p = 0.0003; partial eta squared = 0.18). However, while secondary stress fell among the burnout cluster, it was only for participants in the intervention group; scores increased for those in the waitlist group (p = 0.003; partial eta squared = 0.12). The pre-post-intervention analysis of both groups also showed that burnout fell in the burnout cluster (p = 0.006; partial eta squared = 0.11). At 3-month follow-up, the burnout score was significantly reduced in the intervention group (p = 0.02; partial eta squared = 0.07), and both the acceptance (p = 0.007) and mindfulness scores (p = 0.05; partial eta squared = 0.05) were increased in the baseline burnout cluster. CONCLUSION: FIRECARE may be a useful approach to preventing and reducing burnout among prehospital caregivers.

Transcription induces context-dependent remodeling of chromatin architecture during differentiation.

Metazoan chromosomes are organized into discrete spatial domains (TADs), believed to contribute to the regulation of transcriptional programs. Despite extensive correlation between domain organization and gene activity, a direct mechanistic link is unclear, with perturbation studies often showing little effect. To follow chromatin architecture changes during development, we used Capture Hi-C to interrogate the domains around key differentially expressed genes during mouse thymocyte maturation, uncovering specific remodeling events. Notably, one TAD boundary was broadened to accommodate RNA polymerase elongation past the border, and subdomains were formed around some activated genes without changes in CTCF binding. The ectopic induction of some genes was sufficient to recapitulate domain formation in embryonic stem cells, providing strong evidence that transcription can directly remodel chromatin structure. These results suggest that transcriptional processes drive complex chromosome folding patterns that can be important in certain genomic contexts.

Cumulative dose of epinephrine and mode of death after non-shockable out-of-hospital cardiac arrest: a registry-based study.

BACKGROUND: Epinephrine increases the chances of return of spontaneous circulation (ROSC) in out-of-hospital cardiac arrest (OHCA), especially when the initial rhythm is non-shockable. However, this drug could also worsen the post-resuscitation syndrome (PRS). We assessed the association between epinephrine use during cardiopulmonary resuscitation (CPR) and subsequent intensive care unit (ICU) mortality in patients with ROSC after non-shockable OHCA. METHODS: We used data prospectively collected in the Sudden Death Expertise Center (SDEC) registry (capturing OHCA data located in the Greater Paris area, France) between May 2011 and December 2021. All adults with ROSC after medical, cardiac and non-cardiac causes, non-shockable OHCA admitted to an ICU were included. The mode of death in the ICU was categorized as cardiocirculatory, neurological, or other. RESULTS: Of the 2,792 patients analyzed, there were 242 (8.7%) survivors at hospital discharge, 1,004 (35.9%) deaths from cardiocirculatory causes, 1,233 (44.2%) deaths from neurological causes, and 313 (11.2%) deaths from other etiologies. The cardiocirculatory death group received more epinephrine (4.6 ± 3.8 mg versus 1.7 ± 2.8 mg, 3.2 ± 2.6 mg, and 3.5 ± 3.6 mg for survivors, neurological deaths, and other deaths, respectively; p < 0.001). The proportion of cardiocirculatory death increased linearly (R2 = 0.92, p < 0.001) with cumulative epinephrine doses during CPR (17.7% in subjects who did not receive epinephrine and 62.5% in those who received > 10 mg). In multivariable analysis, a cumulative dose of epinephrine was strongly associated with cardiocirculatory death (adjusted odds ratio of 3.45, 95% CI [2.01-5.92] for 1 mg of epinephrine; 12.28, 95% CI [7.52-20.06] for 2-5 mg; and 23.71, 95% CI [11.02-50.97] for > 5 mg; reference 0 mg; population reference: alive at hospital discharge), even after adjustment on duration of resuscitation. The other modes of death (neurological and other causes) were also associated with epinephrine use, but to a lesser extent. CONCLUSIONS: In non-shockable OHCA with ROSC, the dose of epinephrine used during CPR is strongly associated with early cardiocirculatory death. Further clinical studies aimed at limiting the dose of epinephrine during CPR seem warranted. Moreover, strategies for the prevention and management of PRS should take this dose of epinephrine into consideration for future trials.

Improving EMS response times for out-of-hospital cardiac arrest in urban areas using drone-like vertical take-off and landing air ambulances: An international, simulation-based cohort study.

BACKGROUND: Advances in vertical take-off and landing (VTOL) technologies may enable drone-like crewed air ambulances to rapidly respond to out-of-hospital cardiac arrest (OHCA) in urban areas. We estimated the impact of incorporating VTOL air ambulances on OHCA response intervals in two large urban centres in France and Canada. METHODS: We included adult OHCAs occurring between Jan. 2017-Dec. 2018 within Greater Paris in France and Metro Vancouver in Canada. Both regions utilize tiered OHCA response with basic (BLS)- and advanced life support (ALS)-capable units. We simulated incorporating 1-2 ALS-capable VTOL air ambulances dedicated to OHCA response in each study region, and computed time intervals from call reception by emergency medical services (EMS) to arrival of the: (1) first ALS unit ("call-to-ALS arrival interval"); and (2) first EMS unit ("call-to-first EMS arrival interval"). RESULTS: There were 6,217 OHCAs included during the study period (3,760 in Greater Paris and 2,457 in Metro Vancouver). Historical median call-to-ALS arrival intervals were 21 min [IQR 16-29] in Greater Paris and 12 min [IQR 9-17] in Metro Vancouver, while median call-to-first EMS arrival intervals were 11 min [IQR 8-14] and 7 min [IQR 5-8] respectively. Incorporating 1-2 VTOL air ambulances improved median call-to-ALS arrival intervals to 7-9 min and call-to-first EMS arrival intervals to 6-8 min in both study regions (all P < 0.001). CONCLUSION: VTOL air ambulances dedicated to OHCA response may improve EMS response intervals, with substantial improvements in ALS response metrics.

Trends in survival from out-of-hospital cardiac arrest with a shockable rhythm and its association with bystander resuscitation: a retrospective study.

OBJECTIVE: Over 300 000 cases of out-of-hospital cardiac arrests (OHCAs) occur each year in the USA and Europe. Despite decades of investment and research, survival remains disappointingly low. We report the trends in survival after a ventricular fibrillation/pulseless ventricular tachycardia OHCA, over a 13-year period, in a French urban region, and describe the simultaneous evolution of the rescue system. METHODS: We investigated four 18-month periods between 2005 and 2018. The first period was considered baseline and included patients from the randomised controlled trial 'DEFI 2005'. The three following periods were based on the Paris Sudden Death Expertise Center Registry (France). Inclusion criteria were non-traumatic cardiac arrests treated with at least one external electric shock with an automated external defibrillator from the basic life support team and resuscitated by a physician-staffed ALS team. Primary outcome was survival at hospital discharge with a good neurological outcome. RESULTS: Of 21 781 patients under consideration, 3476 (16%) met the inclusion criteria. Over all study periods, survival at hospital discharge increased from 12% in 2005 to 25% in 2018 (p<0.001), and return of spontaneous circulation at hospital admission increased from 43% to 58% (p=0.004).Lay-rescuer cardiopulmonary resuscitation (CPR) and telephone CPR (T-CPR) rates increased significantly, but public defibrillator use remained limited. CONCLUSION: In a two-tiered rescue system, survival from OHCA at hospital discharge doubled over a 13-year study period. Concomitantly, the system implemented an OHCA patient registry and increased T-CPR frequency, despite a consistently low rate of public defibrillator use.

HP1-driven phase separation recapitulates the thermodynamics and kinetics of heterochromatin condensate formation.

The spatial segregation of pericentromeric heterochromatin (PCH) into distinct, membrane-less nuclear compartments involves the binding of Heterochromatin Protein 1 (HP1) to H3K9me2/3-rich genomic regions. While HP1 exhibits liquid-liquid phase separation properties in vitro, its mechanistic impact on the structure and dynamics of PCH condensate formation in vivo remains largely unresolved. Here, using a minimal theoretical framework, we systematically investigate the mutual coupling between self-interacting HP1-like molecules and the chromatin polymer. We reveal that the specific affinity of HP1 for H3K9me2/3 loci facilitates coacervation in nucleo and promotes the formation of stable PCH condensates at HP1 levels far below the concentration required to observe phase separation in purified protein assays in vitro. These heterotypic HP1-chromatin interactions give rise to a strong dependence of the nucleoplasmic HP1 density on HP1-H3K9me2/3 stoichiometry, consistent with the thermodynamics of multicomponent phase separation. The dynamical cross talk between HP1 and the viscoelastic chromatin scaffold also leads to anomalously slow equilibration kinetics, which strongly depend on the genomic distribution of H3K9me2/3 domains and result in the coexistence of multiple long-lived, microphase-separated PCH compartments. The morphology of these complex coacervates is further found to be governed by the dynamic establishment of the underlying H3K9me2/3 landscape, which may drive their increasingly abnormal, aspherical shapes during cell development. These findings compare favorably to 4D microscopy measurements of HP1 condensate formation in live Drosophila embryos and suggest a general quantitative model of PCH formation based on the interplay between HP1-based phase separation and chromatin polymer mechanics.

Biophysical ordering transitions underlie genome 3D re-organization during cricket spermiogenesis.

Spermiogenesis is a radical process of differentiation whereby sperm cells acquire a compact and specialized morphology to cope with the constraints of sexual reproduction while preserving their main cargo, an intact copy of the paternal genome. In animals, this often involves the replacement of most histones by sperm-specific nuclear basic proteins (SNBPs). Yet, how the SNBP-structured genome achieves compaction and accommodates shaping remain largely unknown. Here, we exploit confocal, electron and super-resolution microscopy, coupled with polymer modeling to identify the higher-order architecture of sperm chromatin in the needle-shaped nucleus of the emerging model cricket Gryllus bimaculatus. Accompanying spermatid differentiation, the SNBP-based genome is strikingly reorganized as ~25nm-thick fibers orderly coiled along the elongated nucleus axis. This chromatin spool is further found to achieve large-scale helical twisting in the final stages of spermiogenesis, favoring its ultracompaction. We reveal that these dramatic transitions may be recapitulated by a surprisingly simple biophysical principle based on a nucleated rigidification of chromatin linked to the histone-to-SNBP transition within a confined nuclear space. Our work highlights a unique, liquid crystal-like mode of higher-order genome organization in ultracompact cricket sperm, and establishes a multidisciplinary methodological framework to explore the diversity of non-canonical modes of DNA organization.

Mobile blood depots in ground ambulances in compliance with French legislation: A feasibility study.

BACKGROUND: Prehospital transfusion is a way of improving the management of hemorrhagic shock. In France, prehospital transfusion is struggling to develop, both because of logistical difficulties and particularly restrictive legislation. To comply with this, we propose to store the blood products (BPs) in ground ambulances with refrigerated boxes allowing remote continuous monitoring of storage conditions, called "NelumBox" (Tec4med Lifescience GmbH). To open them, the ambulance's team needs a code that is only given by the Transfusion Center if the request meets all required regulatory criteria. STUDY DESIGN AND METHODS: We conducted a prospective simulation-based feasibility study using dummy BPs. Two ambulances were equipped. Simulations were triggered unexpectedly, including during on-call hours. The ability to quickly access the BPs was the main judgment criterion. The quality of hemovigilance during these simulations was also examined. RESULTS: Twenty-two simulations were performed. The ambulance's team was able to access the BPs in 100% of cases. The average waiting time for receiving the unlocking code was 5 min 27 s (SD = 2 min 12 s, MAX = 12 min 00 s). The transfusion traceability was compliant with regulations in 100% of cases. The transfusion center was able to remotely monitor BPs storage conditions for the entire duration of their stockage in the NelumBox. DISCUSSION: The present procedure is efficient, repeatable, and fast. It guarantees a strict transfusion safety without slowdown a severe trauma management, while complying with French regulations.

Factors associated with circulatory death after out-of-hospital cardiac arrest: a population-based cluster analysis.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a common cause of death. Early circulatory failure is the most common reason for death within the first 48 h. This study in intensive care unit (ICU) patients with OHCA was designed to identify and characterize clusters based on clinical features and to determine the frequency of death from refractory postresuscitation shock (RPRS) in each cluster. METHODS: We retrospectively identified adults admitted alive to ICUs after OHCA in 2011-2018 and recorded in a prospective registry for the Paris region (France). We identified patient clusters by performing an unsupervised hierarchical cluster analysis (without mode of death among the variables) based on Utstein clinical and laboratory variables. For each cluster, we estimated the hazard ratio (HRs) for RPRS. RESULTS: Of the 4445 included patients, 1468 (33%) were discharged alive from the ICU and 2977 (67%) died in the ICU. We identified four clusters: initial shockable rhythm with short low-flow time (cluster 1), initial non-shockable rhythm with usual absence of ST-segment elevation (cluster 2), initial non-shockable rhythm with long no-flow time (cluster 3), and long low-flow time with high epinephrine dose (cluster 4). RPRS was significantly associated with this last cluster (HR, 5.51; 95% confidence interval 4.51-6.74). CONCLUSIONS: We identified patient clusters based on Utstein criteria, and one cluster was strongly associated with RPRS. This result may help to make decisions about using specific treatments after OHCA.

4D epigenomics: deciphering the coupling between genome folding and epigenomic regulation with biophysical modeling.

Recent experimental observations suggest a strong coupling between the 3D nuclear chromosome organization and epigenomics. However, the mechanistic and functional bases of such interplay remain elusive. In this review, we describe how biophysical modeling has been instrumental in characterizing how genome folding may impact the formation of epigenomic domains and, conversely, how epigenomic marks may affect chromosome conformation. Finally, we discuss how this mutual feedback loop between chromatin organization and epigenome regulation, via the formation of physicochemical nanoreactors, may represent a key functional role of 3D compartmentalization in the assembly and maintenance of stable - but yet plastic - epigenomic landscapes.