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.

Geometric frustration of Jahn-Teller order in the infinite-layer lattice.

The Jahn-Teller effect, in which electronic configurations with energetically degenerate orbitals induce lattice distortions to lift this degeneracy, has a key role in many symmetry-lowering crystal deformations1. Lattices of Jahn-Teller ions can induce a cooperative distortion, as exemplified by LaMnO3 (refs. 2,3). Although many examples occur in octahedrally4 or tetrahedrally5 coordinated transition metal oxides due to their high orbital degeneracy, this effect has yet to be manifested for square-planar anion coordination, as found in infinite-layer copper6,7, nickel8,9, iron10,11 and manganese oxides12. Here we synthesize single-crystal CaCoO2 thin films by topotactic reduction of the brownmillerite CaCoO2.5 phase. We observe a markedly distorted infinite-layer structure, with ångström-scale displacements of the cations from their high-symmetry positions. This can be understood to originate from the Jahn-Teller degeneracy of the dxz and dyz orbitals in the d7 electronic configuration along with substantial ligand-transition metal mixing. A complex pattern of distortions arises in a [Formula: see text] tetragonal supercell, reflecting the competition between an ordered Jahn-Teller effect on the CoO2 sublattice and the geometric frustration of the associated displacements of the Ca sublattice, which are strongly coupled in the absence of apical oxygen. As a result of this competition, the CaCoO2 structure forms an extended two-in-two-out type of Co distortion following 'ice rules'13.

Differential Effect of Targeted Temperature Management Between 32 °C and 36 °C Following Cardiac Arrest According to Initial Severity of Illness: Insights From Two International Data Sets.

BACKGROUND: Recent guidelines have emphasized actively avoiding fever to improve outcomes in patients who are comatose following resuscitation from cardiac arrest (ie, out-of-hospital cardiac arrest). However, whether targeted temperature management between 32 °C and 36 °C (TTM32-36) can improve neurologic outcome in some patients remains debated. RESEARCH QUESTION: Is there an association between the use of TTM32-36 and outcome according to severity assessed at ICU admission using a previously derived risk score? STUDY DESIGN AND METHODS: Data prospectively collected in the Sudden Death Expertise Center (SDEC) registry (France) between May 2011 and December 2017 and in the Resuscitation Outcomes Consortium Continuous Chest Compressions (ROC-CCC) trial (United States and Canada) between June 2011 and May 2015 were used for this study. Severity at ICU admission was assessed through a modified version of the Cardiac Arrest Hospital Prognosis (mCAHP) score, divided into tertiles of severity. The study explored associations between TTM32-36 and favorable neurologic status at hospital discharge by using multiple logistic regression as well as in tertiles of severity for each data set. RESULTS: A total of 2,723 patients were analyzed in the SDEC data set and 4,202 patients in the ROC-CCC data set. A favorable neurologic status at hospital discharge occurred in 728 (27%) patients in the French data set and in 1,239 (29%) patients in the North American data set. Among the French data set, TTM32-36 was independently associated with better neurologic outcome in the tertile of patients with low (adjusted OR, 1.63; 95% CI, 1.15-2.30; P = .006) and high (adjusted OR, 1.94; 95% CI, 1.06-3.54; P = .030) severity according to mCAHP at ICU admission. Similar results were observed in the North American data set (adjusted ORs of 1.36 [95% CI, 1.05-1.75; P = .020] and 2.42 [95% CI, 1.38-4.24; P = .002], respectively). No association was observed between TTM32-36 and outcome in the moderate groups of the two data sets. INTERPRETATION: TTM32-36 was significantly associated with a better outcome in patients with low and high severity at ICU admission assessed according to the mCAHP score. Further studies are needed to evaluate individualized temperature control following out-of-hospital cardiac arrest.

3DPolyS-LE: an accessible simulation framework to model the interplay between chromatin and loop extrusion.

SUMMARY: Recent studies suggest that the loop extrusion activity of Structural Maintenance of Chromosomes complexes is central to proper organization of genomes in vivo. Polymer physics-based modeling of chromosome structure has been instrumental to assess which structures such extrusion can create. Only few laboratories however have the technical and computational expertise to create in silico models combining dynamic features of chromatin and loop extruders. Here, we present 3DPolyS-LE, a self-contained, easy to use modeling and simulation framework allowing non-specialists to ask how specific properties of loop extruders and boundary elements impact on 3D chromosome structure. 3DPolyS-LE also provides algorithms to compare predictions with experimental Hi-C data. AVAILABILITY AND IMPLEMENTATION: Software available at https://gitlab.com/togop/3DPolyS-LE; implemented in Python and Fortran 2003 and supported on any Unix-based operating system (Linux and Mac OS). SUPPLEMENTARY INFORMATION: Supplementary information are available at Bioinformatics online.

Dynamical modeling of the H3K27 epigenetic landscape in mouse embryonic stem cells.

The Polycomb system via the methylation of the lysine 27 of histone H3 (H3K27) plays central roles in the silencing of many lineage-specific genes during development. Recent experimental evidence suggested that the recruitment of histone modifying enzymes like the Polycomb repressive complex 2 (PRC2) at specific sites and their spreading capacities from these sites are key to the establishment and maintenance of a proper epigenomic landscape around Polycomb-target genes. Here, to test whether such mechanisms, as a minimal set of qualitative rules, are quantitatively compatible with data, we developed a mathematical model that can predict the locus-specific distributions of H3K27 modifications based on previous biochemical knowledge. Within the biological context of mouse embryonic stem cells, our model showed quantitative agreement with experimental profiles of H3K27 acetylation and methylation around Polycomb-target genes in wild-type and mutants. In particular, we demonstrated the key role of the reader-writer module of PRC2 and of the competition between the binding of activating and repressing enzymes in shaping the H3K27 landscape around transcriptional start sites. The predicted dynamics of establishment and maintenance of the repressive trimethylated H3K27 state suggest a slow accumulation, in perfect agreement with experiments. Our approach represents a first step towards a quantitative description of PcG regulation in various cellular contexts and provides a generic framework to better characterize epigenetic regulation in normal or disease situations.