Mechanism of homology search expansion during recombinational DNA break repair in Saccharomyces cerevisiae.

Homology search is a central step of DNA double-strand break (DSB) repair by homologous recombination (HR). How it operates in cells remains elusive. We developed a Hi-C-based methodology to map single-stranded DNA (ssDNA) contacts genome-wide in S. cerevisiae, which revealed two main homology search phases. Initial search conducted by short Rad51-ssDNA nucleoprotein filaments (NPFs) is confined in cis by cohesin-mediated chromatin loop folding. Progressive growth of stiff NPFs enables exploration of distant genomic sites. Long-range resection drives this transition from local to genome-wide search by increasing the probability of assembling extensive NPFs. DSB end-tethering promotes coordinated search by opposite NPFs. Finally, an autonomous genetic element on chromosome III engages the NPF, which stimulates homology search in its vicinity. This work reveals the mechanism of the progressive expansion of homology search that is orchestrated by chromatin organizers, long-range resection, end-tethering, and specialized genetic elements and that exploits the stiff NPF structure conferred by Rad51 oligomerization.

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.

4D Genome Rewiring during Oncogene-Induced and Replicative Senescence.

To understand the role of the extensive senescence-associated 3D genome reorganization, we generated genome-wide chromatin interaction maps, epigenome, replication-timing, whole-genome bisulfite sequencing, and gene expression profiles from cells entering replicative senescence (RS) or upon oncogene-induced senescence (OIS). We identify senescence-associated heterochromatin domains (SAHDs). Differential intra- versus inter-SAHD interactions lead to the formation of senescence-associated heterochromatin foci (SAHFs) in OIS but not in RS. This OIS-specific configuration brings active genes located in genomic regions adjacent to SAHDs in close spatial proximity and favors their expression. We also identify DNMT1 as a factor that induces SAHFs by promoting HMGA2 expression. Upon DNMT1 depletion, OIS cells transition to a 3D genome conformation akin to that of cells in replicative senescence. These data show how multi-omics and imaging can identify critical features of RS and OIS and discover determinants of acute senescence and SAHF formation.

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.

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.

Spatial organization of chromosomes leads to heterogeneous chromatin motion and drives the liquid- or gel-like dynamical behavior of chromatin.

Chromosome organization and dynamics are involved in regulating many fundamental processes such as gene transcription and DNA repair. Experiments unveiled that chromatin motion is highly heterogeneous inside cell nuclei, ranging from a liquid-like, mobile state to a gel-like, rigid regime. Using polymer modeling, we investigate how these different physical states and dynamical heterogeneities may emerge from the same structural mechanisms. We found that the formation of topologically associating domains (TADs) is a key driver of chromatin motion heterogeneity. In particular, we showed that the local degree of compaction of the TAD regulates the transition from a weakly compact, fluid state of chromatin to a more compact, gel state exhibiting anomalous diffusion and coherent motion. Our work provides a comprehensive study of chromosome dynamics and a unified view of chromatin motion enabling interpretation of the wide variety of dynamical behaviors observed experimentally across different biological conditions, suggesting that the "liquid" or "solid" state of chromatin are in fact two sides of the same coin.

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.

Painters in chromatin: a unified quantitative framework to systematically characterize epigenome regulation and memory.

In eukaryotes, many stable and heritable phenotypes arise from the same DNA sequence, owing to epigenetic regulatory mechanisms relying on the molecular cooperativity of 'reader-writer' enzymes. In this work, we focus on the fundamental, generic mechanisms behind the epigenome memory encoded by post-translational modifications of histone tails. Based on experimental knowledge, we introduce a unified modeling framework, the painter model, describing the mechanistic interplay between sequence-specific recruitment of chromatin regulators, chromatin-state-specific reader-writer processes and long-range spreading mechanisms. A systematic analysis of the model building blocks highlights the crucial impact of tridimensional chromatin organization and state-specific recruitment of enzymes on the stability of epigenomic domains and on gene expression. In particular, we show that enhanced 3D compaction of the genome and enzyme limitation facilitate the formation of ultra-stable, confined chromatin domains. The model also captures how chromatin state dynamics impact the intrinsic transcriptional properties of the region, slower kinetics leading to noisier expression. We finally apply our framework to analyze experimental data, from the propagation of γH2AX around DNA breaks in human cells to the maintenance of heterochromatin in fission yeast, illustrating how the painter model can be used to extract quantitative information on epigenomic molecular processes.

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.

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.

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.

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.

Polymer modelling unveils the roles of heterochromatin and nucleolar organizing regions in shaping 3D genome organization in Arabidopsis thaliana.

The 3D genome is characterized by a complex organization made of genomic and epigenomic layers with profound implications on gene regulation and cell function. However, the understanding of the fundamental mechanisms driving the crosstalk between nuclear architecture and (epi)genomic information is still lacking. The plant Arabidopsis thaliana is a powerful model organism to address these questions owing to its compact genome for which we have a rich collection of microscopy, chromosome conformation capture (Hi-C) and ChIP-seq experiments. Using polymer modelling, we investigate the roles of nucleolus formation and epigenomics-driven interactions in shaping the 3D genome of A. thaliana. By validation of several predictions with published data, we demonstrate that self-attracting nucleolar organizing regions and repulsive constitutive heterochromatin are major mechanisms to regulate the organization of chromosomes. Simulations also suggest that interphase chromosomes maintain a partial structural memory of the V-shapes, typical of (sub)metacentric chromosomes in anaphase. Additionally, self-attraction between facultative heterochromatin regions facilitates the formation of Polycomb bodies hosting H3K27me3-enriched gene-clusters. Since nucleolus and heterochromatin are highly-conserved in eukaryotic cells, our findings pave the way for a comprehensive characterization of the generic principles that are likely to shape and regulate the 3D genome in many species.

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.

Association between prehospital shock index and mortality among patients with COVID-19 disease.

BACKGROUND: There exists a need for prognostic tools for the early identification of COVID-19 patients requiring intensive care unit (ICU) admission and mortality. Here we investigated the association between a clinical (initial prehospital shock index (SI)) and biological (initial prehospital lactatemia) tool and the ICU admission and 30-day mortality among COVID-19 patients cared for in the prehospital setting. METHODS: We retrospectively analysed COVID-19 patients initially cared for by a Paris Fire Brigade advanced (ALS) or basic life support (BLS) team in the prehospital setting between 2020, March 08th and 2020, May 30th. We assessed the association between prehospital SI and prehospital lactatemia and ICU admission and mortality using logistic regression model analysis after propensity score matching with Inverse Probability Treatment Weighting (IPTW) method. Covariates included in the IPTW propensity analysis were: age, sex, body mass index (BMI), initial respiratory rate (iRR), initial pulse oximetry without (SpO2i) and with oxygen supplementation (SpO2i.O2), initial Glasgow coma scale (GCSi) value, initial prehospital SI and initial prehospital lactatemia. RESULTS: We analysed 410 consecutive COVID-19 patients [254 males (62%); mean age, 64 ± 18 years]. Fifty-seven patients (14%) deceased on the scene, of whom 41 (72%) were male and were significantly older (71 ± 12 years vs. 64 ± 19 years; P 〈10-3). Fifty-three patients (15%) were admitted in ICU and 39 patients (11%) were deceased on day-30. The mean prehospital SI value was 1.5 ± 0.4 and the mean prehospital lactatemia was 2.0 ± 1.7 mmol.l-1. Multivariate logistic regression analysis on matched population after IPTW propensity analysis reported a significant association between ICU admission and age (adjusted Odd-Ratio (aOR), 0.90; 95% confidence interval (95%CI): 0.93-0.98;p = 10-3), SpO2i.O2 (aOR, 1.10; 95%CI: 1.02-1.20;p = 0.002) and BMI (aOR, 1.09; 95% CI: 1.03-1.16;p = 0.02). 30-day mortality was significantly associated with SpO2i.O2 (aOR, 0.92; 95% CI: 0.87-0.98;p = 0.01 P < 10-3) and GCSi (aOR, 0.90; 95% CI: 0.82-0.99;p = 0.04). Neither prehospital SI nor prehospital lactatemia were associated with ICU admission and 30-day mortality. CONCLUSION: Neither prehospital initial SI nor lactatemia were associated with ICU admission and 30-day mortality among COVID-19 patients initially cared for by a Paris Fire Brigade BLS or ALS team. Further prospective studies are needed to confirm these preliminary results.

Assessment of emergency physicians' performance in identifying shockable rhythm in out-of-hospital cardiac arrest: an observational simulation study.

BACKGROUND: Emergency physicians can use a manual or an automated defibrillator to provide defibrillation of patients who had out-of-hospital cardiac arrest (OHCA). Performance of emergency physicians in identifying shockable rhythm with a manual defibrillator has been poorly explored whereas that of automated defibrillators is well known (sensitivity 0.91-1.00, specificity 0.96-0.99). We conducted this study to estimate the sensitivity/specificity and speed of shock/no-shock decision-making by prehospital emergency physicians for shockable or non-shockable rhythm, and their preference for manual versus automated defibrillation. METHODS: We developed a web application that simulates a manual defibrillator (https://simul-shock.firebaseapp.com/). In 2019, all (262) emergency physicians of six French emergency medical services were invited to participate in a study in which 60 ECG rhythms from real OHCA recordings were successively presented to the physicians for determination of whether they would or would not administer a shock. Time to decision was recorded. Answers were compared with a gold standard (concordant answers of three experts). We report sensitivity for shockable rhythms (decision to shock) and specificity for non-shockable rhythms (decision not to shock). Physicians were also asked whether they preferred manual or automated defibrillation. RESULTS: Among 215 respondents, we were able to analyse results for 190 physicians. 57% of emergency physicians preferred manual defibrillation. Median (IQR) sensitivity for a shock delivery for shockable rhythm was 0.91 (0.81-1.00); median specificity for no-shock delivery for non-shockable rhythms was 0.91 (0.80-0.96). More precisely, sensitivities for shock delivery for ventricular tachycardia (VT) and coarse ventricular fibrillation (VF) were both 1.0 (1.0-1.0); sensitivity for fine VF was 0.6 (0.2-1). Specificity for not shocking a pulseless electrical activity (PEA) was 0.83 (0.72-0.86), and for asystole, specificity was 0.93 (0.86-1). Median speed of decision-making (in seconds) were: VT 2.0 (1.6-2.7), coarse VF 2.1 (1.7-2.9), asystole 2.4 (1.8-3.5), PEA 2.8 (2.0-4.2) and fine VF 2.8 (2.1-4.3). CONCLUSIONS: Global sensitivity and specificity were comparable with published automated external defibrillator studies. Shockable rhythms with the best clinical prognoses (VT and coarse VF) were very rapidly recognised with very good sensitivity. The decision-making for fine VF or asystole and PEA was less accurate.

Differential spatial and structural organization of the X chromosome underlies dosage compensation in C. elegans.

The adjustment of X-linked gene expression to the X chromosome copy number (dosage compensation [DC]) has been widely studied as a model of chromosome-wide gene regulation. In Caenorhabditis elegans, DC is achieved by twofold down-regulation of gene expression from both Xs in hermaphrodites. We show that in males, the single X chromosome interacts with nuclear pore proteins, while in hermaphrodites, the DC complex (DCC) impairs this interaction and alters X localization. Our results put forward a structural model of DC in which X-specific sequences locate the X chromosome in transcriptionally active domains in males, while the DCC prevents this in hermaphrodites.

PenDA, a rank-based method for personalized differential analysis: Application to lung cancer.

The hopes of precision medicine rely on our capacity to measure various high-throughput genomic information of a patient and to integrate them for personalized diagnosis and adapted treatment. Reaching these ambitious objectives will require the development of efficient tools for the detection of molecular defects at the individual level. Here, we propose a novel method, PenDA, to perform Personalized Differential Analysis at the scale of a single sample. PenDA is based on the local ordering of gene expressions within individual cases and infers the deregulation status of genes in a sample of interest compared to a reference dataset. Based on realistic simulations of RNA-seq data of tumors, we showed that PenDA outcompetes existing approaches with very high specificity and sensitivity and is robust to normalization effects. Applying the method to lung cancer cohorts, we observed that deregulated genes in tumors exhibit a cancer-type-specific commitment towards up- or down-regulation. Based on the individual information of deregulation given by PenDA, we were able to define two new molecular histologies for lung adenocarcinoma cancers strongly correlated to survival. In particular, we identified 37 biomarkers whose up-regulation lead to bad prognosis and that we validated on two independent cohorts. PenDA provides a robust, generic tool to extract personalized deregulation patterns that can then be used for the discovery of therapeutic targets and for personalized diagnosis. An open-access, user-friendly R package is available at https://github.com/bcm-uga/penda.

Prehospital management of acute respiratory distress in suspected COVID-19 patients.

BACKGROUND: In December 2019, coronavirus disease (COVID-19) emerged in China and became a world-wide pandemic in March 2020. Emergency services and intensive care units (ICUs) were faced with a novel disease with unknown clinical characteristics and presentations. Acute respiratory distress (ARD) was often the chief complaint for an EMS call. This retrospective study evaluated prehospital ARD management and identified factors associated with the need of prehospital mechanical ventilation (PMV) for suspected COVID-19 patients. METHODS: We included 256 consecutive patients with suspected COVID-19-related ARD that received prehospital care from a Paris Fire Brigade BLS or ALS team, from March 08 to April 18, 2020. We performed multivariate regression to identify factors predisposing to PMV. RESULTS: Of 256 patients (mean age 60 ± 18 years; 82 (32%) males), 77 (30%) had previous hypertension, 31 (12%) were obese, and 49 (19%) had diabetes mellitus. Nineteen patients (7%) required PMV. Logistic regression observed that a low initial pulse oximetry was associated with prehospital PMV (ORa = 0.86, 95%CI: 0.73-0.92; p = 0.004). CONCLUSIONS: This study showed that pulse oximetry might be a valuable marker for rapidly determining suspected COVID-19-patients requiring prehospital mechanical ventilation. Nevertheless, the impact of prehospital mechanical ventilation on COVID-19 patients outcome require further investigations.