Assessing Pandemic Preparedness, Response, and Lessons Learned From the Covid-19 Pandemic in Four South American Countries: Agenda for the Future

INTRODUCTION: The COVID-19 pandemic emerged in a context that lacked adequate prevention, preparedness, and response (PPR) activities, and global, regional, and national leadership. South American countries were among world\u27s hardest hit by the pandemic, accounting for 10.1% of total cases and 20.1% of global deaths. METHODS: This study explores how pandemic PPR were affected by political, socioeconomic, and health system contexts as well as how PPR may have shaped pandemic outcomes in Argentina, Brazil, Colombia, and Peru. We then identify lessons learned and advance an agenda for improving PPR capacity at regional and national levels. We do this through a mixed-methods sequential explanatory study in four South American countries based on structured interviews and focus groups with elite policy makers. RESULTS: The results of our study demonstrate that structural and contextual barriers limited PPR activities at political, social, and economic levels in each country, as well as through the structure of the health care system. Respondents believe that top-level government officials had insufficient political will for prioritizing pandemic PPR and post-COVID-19 recovery programs within their countries\u27 health agendas. DISCUSSION: We recommend a regional COVID-19 task force, post-pandemic recovery, social and economic protection for vulnerable groups, improved primary health care and surveillance systems, risk communication strategies, and community engagement to place pandemic PPR on Argentina, Brazil, Colombia, and Peru and other South American countries\u27 national public health agendas

Bone Marrow Clonogenic Myeloid Progenitors from NPM1-Mutated AML Patients Do Not Harbor the NPM1 Mutation: Implication for the Cell-Of-Origin of NPM1+ AML

The cell-of-origin of NPM1- and FLT3-mutated acute myeloid leukemia (AML) is still a matter of debate. Here, we combined in vitro clonogenic assays with targeted sequencing to gain further insights into the cell-of-origin of NPM1 and FLT3-ITD-mutated AML in diagnostic bone marrow (BM) from nine NPM1+/FLT3-ITD (+/-) AMLs. We reasoned that individually plucked colony forming units (CFUs) are clonal and reflect the progeny of a single stem/progenitor cell. NPM1 and FLT3-ITD mutations seen in the diagnostic blasts were found in only 2/95 and 1/57 individually plucked CFUs, suggesting that BM clonogenic myeloid progenitors in NPM1-mutated and NPM1/FLT3-ITD-mutated AML patients do not harbor such molecular lesions. This supports previous studies on NPM1 mutations as secondary mutations in AML, likely acquired in an expanded pool of committed myeloid progenitors, perhaps CD34-, in line with the CD34-/low phenotype of NPM1-mutated AMLs. This study has important implications on the cell-of-origin of NPM1+ AML, and reinforces that therapeutic targeting of either NPM1 or FLT3-ITD mutations might only have a transient clinical benefit in debulking the leukemia, but is unlikely to be curative since will not target the AML-initiating/preleukemic cells. The absence of NPM1 and FLT3-ITD mutations in normal clonogenic myeloid progenitors is in line with their absence in clonal hematopoiesis of indeterminate potential.We thank CERCA/Generalitat de Catalunya and Fundació Josep Carreras-Obra Social la Caixa for their institutional support. Financial support for this work was obtained from the Generalitat de Catalunya (SGR330) to P.M., the Spanish Ministry of Economy and Competitiveness (SAF2016-80481-R to P.M. and SAF2016-76758-R to I.V.), the Fundación Uno entre Cienmil, the Obra Social La Caixa (ID 100010434, under agreement LCF/PR/HR19/52160011), the Josep Carreras Foundation, the Leo Messi Foundation, and the Banco Santander Foundation to P.M.; and the Spanish Association against cancer (AECC-CI-2015) to C.B. E.A. acknowledges support form “Fundación Hay Esperanza”. P.M. is an investigator of the Spanish Cell Therapy cooperative network (TERCEL)

The HDAC7-TET2 epigenetic axis is essential during early B lymphocyte development

Correct B cell identity at each stage of cellular differentiation during B lymphocyte development is critically dependent on a tightly controlled epigenomic landscape. We previously identified HDAC7 as an essential regulator of early B cell development and its absence leads to a drastic block at the pro-B to pre-B cell transition. More recently, we demonstrated that HDAC7 loss in pro-B-ALL in infants associates with a worse prognosis. Here we delineate the molecular mechanisms by which HDAC7 modulates early B cell development. We find that HDAC7 deficiency drives global chromatin de-condensation, histone marks deposition and deregulates other epigenetic regulators and mobile elements. Specifically, the absence of HDAC7 induces TET2 expression, which promotes DNA 5-hydroxymethylation and chromatin de-condensation. HDAC7 deficiency also results in the aberrant expression of microRNAs and LINE-1 transposable elements. These findings shed light on the mechanisms by which HDAC7 loss or misregulation may lead to B cell-based hematological malignancies.FUNDING: Spanish Ministry of Economy and Competitiveness (MINECO) [SAF2017-87990-R]; Spanish Ministry of Science and Innovation (MICINN) [EUR2019-103835]; Josep Carreras Leukaemia Research Institute (IJC, Badalona, Barcelona); IDIBELL Research Institute (L’Hospitalet de Llobregat, Barcelona); A.M. is funded by the Spanish Ministry of Science, Innovation and Universities, which is part of the Agencia Estatal de Investigacion (AEI) [PRE2018-083183] (cofunded by the European Social Fund]; OdB. was funded by a Juan de la Cierva Formacion Fellowship from the Spanish Ministry of Science, Innovation and Universities [FJCI-2017-32430]; Postdoctoral Fellowship from the Asociacion Española Contra el Cáncer (AECC) ´ Foundation [POSTD20024DEBA]; B.M. is awardee of the Ayudas para la formacion del profesorado universitario [FPU18/00755, Ministerio de Universidades]; B.M.J. is funded by La Caixa Banking Foundation Junior Leader project [LCF/BQ/PI19/11690001]; FEDER/Spanish Ministry of Science and Innovation [RTI2018-094788-A-I00]; L.T.-D. is funded by the FPI Fellowship [PRE2019- 088005]; L.R. is funded by an AGAUR FI fellowship [2019FI-B00017]; J.L.S. is funded by ISCIII [CP19/00176], co-funded by ESF, ‘Investing in your future’ and the Spanish Ministry of Science, Innovation and Universities [PID2019-111243RA-I00]. CRG acknowledge the support of the Spanish Ministry of Science and Innovation through the Centro de Excelencia Severo Ochoa (CEX2020-001049- S, MCIN/AEI /10.13039/501100011033). Funding for open access charge: Spanish Ministry of Science, Innovation and Universities (MICIU) [SAF2017-87990-R, EUR2019-103835].ACKNOWLEDGEMENTS: We thank CERCA Programme/Generalitat de Catalunya and the Josep Carreras Foundation for institutional support. We thank Dr Eric Olson (UT Southwestern Medical Center, Dallas, TX, USA) and Dr Michael Reth (Max Planck Institute of Immunology and Epigenetics, Freiburg, Germany) for kindly providing the Hdac7loxp/- and mb1- Cre mice, respectively. We thank Luc´ıa Fanlo for her assistance in technical issues and bioinformatics analysis of ChIP-seq and ATAC-seq experiments. We thank Alberto Bueno for deep analysis of our RNA-seq and hMeDIP-seq data, in order to assess the presence of differentially expressed dsRNA species. We also thank Drs Pura Munoz ˜ Canoves and Tokameh Mahmoudi for helpful comments on ´ the manuscript

Selective Adaptation in Networks of Heterogeneous Populations: Model, Simulation, and Experiment

Biological systems often change their responsiveness when subject to persistent stimulation, a phenomenon termed adaptation. In neural systems, this process is often selective, allowing the system to adapt to one stimulus while preserving its sensitivity to another. In some studies, it has been shown that adaptation to a frequent stimulus increases the system's sensitivity to rare stimuli. These phenomena were explained in previous work as a result of complex interactions between the various subpopulations of the network. A formal description and analysis of neuronal systems, however, is hindered by the network's heterogeneity and by the multitude of processes taking place at different time-scales. Viewing neural networks as populations of interacting elements, we develop a framework that facilitates a formal analysis of complex, structured, heterogeneous networks. The formulation developed is based on an analysis of the availability of activity dependent resources, and their effects on network responsiveness. This approach offers a simple mechanistic explanation for selective adaptation, and leads to several predictions that were corroborated in both computer simulations and in cultures of cortical neurons developing in vitro. The framework is sufficiently general to apply to different biological systems, and was demonstrated in two different cases

Synaptic Transmission and Plasticity in an Active Cortical Network

BACKGROUND: The cerebral cortex is permanently active during both awake and sleep states. This ongoing cortical activity has an impact on synaptic transmission and short-term plasticity. An activity pattern generated by the cortical network is a slow rhythmic activity that alternates up (active) and down (silent) states, a pattern occurring during slow wave sleep, anesthesia and even in vitro. Here we have studied 1) how network activity affects short term synaptic plasticity and, 2) how synaptic transmission varies in up versus down states. METHODOLOGY/PRINCIPAL FINDINGS: Intracellular recordings obtained from cortex in vitro and in vivo were used to record synaptic potentials, while presynaptic activation was achieved either with electrical or natural stimulation. Repetitive activation of layer 4 to layer 2/3 synaptic connections from ferret visual cortex slices displayed synaptic augmentation that was larger and longer lasting in active than in silent slices. Paired-pulse facilitation was also significantly larger in an active network and it persisted for longer intervals (up to 200 ms) than in silent slices. Intracortical synaptic potentials occurring during up states in vitro increased their amplitude while paired-pulse facilitation disappeared. Both intracortical and thalamocortical synaptic potentials were also significantly larger in up than in down states in the cat visual cortex in vivo. These enhanced synaptic potentials did not further facilitate when pairs of stimuli were given, thus paired-pulse facilitation during up states in vivo was virtually absent. Visually induced synaptic responses displayed larger amplitudes when occurring during up versus down states. This was further tested in rat barrel cortex, where a sensory activated synaptic potential was also larger in up states. CONCLUSIONS/SIGNIFICANCE: These results imply that synaptic transmission in an active cortical network is more secure and efficient due to larger amplitude of synaptic potentials and lesser short term plasticity

Cell free circulating tumor DNA in cerebrospinal fluid detects and monitors central nervous system involvement of B-cell lymphomas

Limfoma no Hodgkin agressiu; Limfoma del SNCLinfoma no Hodgkin agresivo; Linfoma del SNCAggressive Non-Hodgkin's Lymphoma; CNS lymphomaThe levels of cell free circulating tumor DNA (ctDNA) in plasma correlated with treatment response and outcome in systemic lymphomas. Notably, in brain tumors, the levels of ctDNA in the cerebrospinal fluid (CSF) are higher than in plasma. Nevertheless, their role in central nervous system (CNS) lymphomas remains elusive. We evaluated the CSF and plasma from 19 patients: 6 restricted CNS lymphomas, 1 systemic and CNS lymphoma, and 12 systemic lymphomas. We performed whole exome sequencing or targeted sequencing to identify somatic mutations of the primary tumor, then variant-specific droplet digital PCR was designed for each mutation. At time of enrolment, we found ctDNA in the CSF of all patients with restricted CNS lymphoma but not in patients with systemic lymphoma without CNS involvement. Conversely, plasma ctDNA was detected in only 2/6 patients with restricted CNS lymphoma with lower variant allele frequencies than CSF ctDNA. Moreover, we detected CSF ctDNA in 1 patient with CNS lymphoma in complete remission and in 1 patient with systemic lymphoma, 3 and 8 months before CNS relapse was confirmed; indicating CSF ctDNA might detect CNS relapse earlier than conventional methods. Finally, in 2 cases with CNS lymphoma, CSF ctDNA was still detected after treatment even though a complete decrease in CSF tumor cells was observed by flow cytometry (FC), indicating CSF ctDNA better detected residual disease than FC. In conclusion, CSF ctDNA can better detect CNS lesions than plasma ctDNA and FC. In addition, CSF ctDNA predicted CNS relapse in CNS and systemic lymphomas.This work was supported by research funding from Fundación Asociación Española contra el Cáncer (AECC) (to JS, MC and PA); FERO (to JS), laCaixa (to JS), BBVA (CAIMI) (to JS), the Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias (PI16/01278 to JS; PI17/00950 to MC; PI17/00943 to FB) cofinanced by the European Regional Development Fund (ERDF) and Gilead Fellowships (GLD16/00144, GLD18/00047, to FB). MC holds a contract from Ministerio de Ciencia, Innovación y Universidades (RYC-2012-12018). SB received funding from Fundación Alfonso Martin Escudero. LE received funding from the Juan de la Cierva fellowship. We thank CERCA Programme / Generalitat de Catalunya for institutional support

Assessing pandemic preparedness, response, and lessons learned from the COVID-19 pandemic in four south American countries: agenda for the future

IntroductionThe COVID-19 pandemic emerged in a context that lacked adequate prevention, preparedness, and response (PPR) activities, and global, regional, and national leadership. South American countries were among world’s hardest hit by the pandemic, accounting for 10.1% of total cases and 20.1% of global deaths.MethodsThis study explores how pandemic PPR were affected by political, socioeconomic, and health system contexts as well as how PPR may have shaped pandemic outcomes in Argentina, Brazil, Colombia, and Peru. We then identify lessons learned and advance an agenda for improving PPR capacity at regional and national levels. We do this through a mixed-methods sequential explanatory study in four South American countries based on structured interviews and focus groups with elite policy makers.ResultsThe results of our study demonstrate that structural and contextual barriers limited PPR activities at political, social, and economic levels in each country, as well as through the structure of the health care system. Respondents believe that top-level government officials had insufficient political will for prioritizing pandemic PPR and post-COVID-19 recovery programs within their countries’ health agendas.DiscussionWe recommend a regional COVID-19 task force, post-pandemic recovery, social and economic protection for vulnerable groups, improved primary health care and surveillance systems, risk communication strategies, and community engagement to place pandemic PPR on Argentina, Brazil, Colombia, and Peru and other South American countries’ national public health agendas

Single hadron response measurement and calorimeter jet energy scale uncertainty with the ATLAS detector at the LHC

The uncertainty on the calorimeter energy response to jets of particles is derived for the ATLAS experiment at the Large Hadron Collider (LHC). First, the calorimeter response to single isolated charged hadrons is measured and compared to the Monte Carlo simulation using proton-proton collisions at centre-of-mass energies of sqrt(s) = 900 GeV and 7 TeV collected during 2009 and 2010. Then, using the decay of K_s and Lambda particles, the calorimeter response to specific types of particles (positively and negatively charged pions, protons, and anti-protons) is measured and compared to the Monte Carlo predictions. Finally, the jet energy scale uncertainty is determined by propagating the response uncertainty for single charged and neutral particles to jets. The response uncertainty is 2-5% for central isolated hadrons and 1-3% for the final calorimeter jet energy scale.Comment: 24 pages plus author list (36 pages total), 23 figures, 1 table, submitted to European Physical Journal