50,339 research outputs found

    International Consensus Criteria for Pediatric Sepsis and Septic Shock.

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    ImportanceSepsis is a leading cause of death among children worldwide. Current pediatric-specific criteria for sepsis were published in 2005 based on expert opinion. In 2016, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection, but it excluded children.ObjectiveTo update and evaluate criteria for sepsis and septic shock in children.Evidence reviewThe Society of Critical Care Medicine (SCCM) convened a task force of 35 pediatric experts in critical care, emergency medicine, infectious diseases, general pediatrics, nursing, public health, and neonatology from 6 continents. Using evidence from an international survey, systematic review and meta-analysis, and a new organ dysfunction score developed based on more than 3 million electronic health record encounters from 10 sites on 4 continents, a modified Delphi consensus process was employed to develop criteria.FindingsBased on survey data, most pediatric clinicians used sepsis to refer to infection with life-threatening organ dysfunction, which differed from prior pediatric sepsis criteria that used systemic inflammatory response syndrome (SIRS) criteria, which have poor predictive properties, and included the redundant term, severe sepsis. The SCCM task force recommends that sepsis in children be identified by a Phoenix Sepsis Score of at least 2 points in children with suspected infection, which indicates potentially life-threatening dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems. Children with a Phoenix Sepsis Score of at least 2 points had in-hospital mortality of 7.1% in higher-resource settings and 28.5% in lower-resource settings, more than 8 times that of children with suspected infection not meeting these criteria. Mortality was higher in children who had organ dysfunction in at least 1 of 4-respiratory, cardiovascular, coagulation, and/or neurological-organ systems that was not the primary site of infection. Septic shock was defined as children with sepsis who had cardiovascular dysfunction, indicated by at least 1 cardiovascular point in the Phoenix Sepsis Score, which included severe hypotension for age, blood lactate exceeding 5 mmol/L, or need for vasoactive medication. Children with septic shock had an in-hospital mortality rate of 10.8% and 33.5% in higher- and lower-resource settings, respectively.Conclusions and relevanceThe Phoenix sepsis criteria for sepsis and septic shock in children were derived and validated by the international SCCM Pediatric Sepsis Definition Task Force using a large international database and survey, systematic review and meta-analysis, and modified Delphi consensus approach. A Phoenix Sepsis Score of at least 2 identified potentially life-threatening organ dysfunction in children younger than 18 years with infection, and its use has the potential to improve clinical care, epidemiological assessment, and research in pediatric sepsis and septic shock around the world

    Predicting the next pandemic: VACCELERATE ranking of the World Health Organization's Blueprint for Action to Prevent Epidemics

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    Introduction: The World Health Organization (WHO)'s Research and Development (R&D) Blueprint for Action to Prevent Epidemics, a plan of action, highlighted several infectious diseases as crucial targets for prevention. These infections were selected based on a thorough assessment of factors such as transmissibility, infectivity, severity, and evolutionary potential. In line with this blueprint, the VACCELERATE Site Network approached infectious disease experts to rank the diseases listed in the WHO R&D Blueprint according to their perceived risk of triggering a pandemic. VACCELERATE is an EU-funded collaborative European network of clinical trial sites, established to respond to emerging pandemics and enhance vaccine development capabilities. Methods: Between February and June 2023, a survey was conducted using an online form to collect data from members of the VACCELERATE Site Network and infectious disease experts worldwide. Participants were asked to rank various pathogens based on their perceived risk of causing a pandemic, including those listed in the WHO R&D Blueprint and additional pathogens. Results: A total of 187 responses were obtained from infectious disease experts representing 57 countries, with Germany, Spain, and Italy providing the highest number of replies. Influenza viruses received the highest rankings among the pathogens, with 79 % of participants including them in their top rankings. Disease X, SARS-CoV-2, SARS-CoV, and Ebola virus were also ranked highly. Hantavirus, Lassa virus, Nipah virus, and henipavirus were among the bottom-ranked pathogens in terms of pandemic potential. Conclusion: Influenza, SARS-CoV, SARS-CoV-2, and Ebola virus were found to be the most concerning pathogens with pandemic potential, characterised by transmissibility through respiratory droplets and a reported history of epidemic or pandemic outbreaks

    Discovery of CMX990: A Potent SARS-CoV‑2 3CL Protease Inhibitor Bearing a Novel Warhead

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    There remains a need to develop novel SARS-CoV-2 therapeutic options that improve upon existing therapies by an increased robustness of response, fewer safety liabilities, and global-ready accessibility. Functionally critical viral main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target due to its homology within the coronaviral family, and lack thereof toward human proteases. In this disclosure, we outline the advent of a novel SARS-CoV-2 3CLpro inhibitor, CMX990, bearing an unprecedented trifluoromethoxymethyl ketone warhead. Compared with the marketed drug nirmatrelvir (combination with ritonavir = Paxlovid), CMX990 has distinctly differentiated potency (∼5× more potent in primary cells) and human in vitro clearance (>4× better microsomal clearance and >10× better hepatocyte clearance), with good in vitro-to-in vivo correlation. Based on its compelling preclinical profile and projected once or twice a day dosing supporting unboosted oral therapy in humans, CMX990 advanced to a Phase 1 clinical trial as an oral drug candidate for SARS-CoV-2

    Preliminary evidence for the importance of therapeutic alliance in MDMA-assisted psychotherapy for posttraumatic stress disorder

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    Background: MDMA-assisted psychotherapy (MDMA-AP) is a combined psychotherapeutic and pharmacologic intervention that shows promise in the treatment of posttraumatic stress disorder (PTSD). Although therapeutic alliance has been established as a key predictor across psychotherapies and is emphasised within MDMA-AP treatment manuals, research has not yet examined the relationship between therapeutic alliance and MDMA-AP treatment outcomes. Objective: Examine whether therapeutic alliance predicts changes in PTSD symptoms following MDMA-AP. Method: Twenty-three individuals with chronic PTSD participated in a MDMA-AP clinical trial that included a randomised (MDMA vs. placebo) and open-label phase. The present analyses focused on participants who were administered MDMA over the course of the randomised and open-label phases (n = 22). Therapeutic alliance was assessed using the Working Alliance Inventory at sessions baseline (pre-session 3) and sessions 4 and 9. PTSD symptoms were assessed using the Clinician Administered PTSD Scale and the Impact of Events Scale-Revised. Results: Controlling for baseline clinician-assessed PTSD severity, therapeutic alliance at sessions 4 and 9 (but not baseline) significantly predicted post-MDMA-AP clinician-assessed PTSD severity. Controlling for baseline self-reported PTSD severity, therapeutic alliance at baseline (although this did not survive correction for multiple comparisons) and sessions 4 and 9 predicted post-MDMA-AP self-reported PTSD severity. Conclusions: The present results provide the first preliminary evidence for the relationship between the therapeutic alliance and treatment outcomes within MDMA-AP for PTSD. These findings highlight the important role of psychotherapy, and common psychotherapeutic factors, within MDMA-AP. Replication in studies with larger and more diverse clinical samples remain necessary. Trial registration:ClinicalTrials.gov identifier: NCT00090064. Among individuals with chronic posttraumatic stress disorder, therapeutic alliance predicted changes in posttraumatic stress disorder severity following MDMA-assisted psychotherapy.Therapeutic alliance may play a key role in facilitating therapeutic improvement within MDMA-assisted psychotherapy.Further research remains necessary to confirm these preliminary findings and the role of therapeutic alliance in MDMA-assisted psychotherapy. Among individuals with chronic posttraumatic stress disorder, therapeutic alliance predicted changes in posttraumatic stress disorder severity following MDMA-assisted psychotherapy. Therapeutic alliance may play a key role in facilitating therapeutic improvement within MDMA-assisted psychotherapy. Further research remains necessary to confirm these preliminary findings and the role of therapeutic alliance in MDMA-assisted psychotherapy.</p

    Orphan crops of archaeology-based crop history research

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    So-called ‘forgotten’ or ‘orphan’ crops are an important component of strategies aimed at preserving and promoting biodiversity. Knowledge of historical cultivation, usage, and geographic and evolutionary trajectories of plants, that is, crop history research, is important for the long-term success of such efforts. However, research biases in the crops chosen for study may present hurdles. This review attempts to systematically identify patterns in crop species representativeness within archaeology-based crop history research. A meta-analysis and synthesis of archaeo- botanical evidence (and lack thereof) is presented for 268 species known to have been cultivated for food prior to 1492 CE from the Mediterranean region to South Asia. We identified 39 genera with known crop plants in this geographical and histor- ical context that are currently absent from its archaeobotanical record, constituting ‘orphan’ crops of archaeobotany. In addition, a worldwide synthesis of crop species studied using geometric morphometric, archaeogenetic and stable isotope analyses of archaeological plant remains is presented, and biases in the species represented in these disciplines are discussed. Both disciplinary methodological biases and economic agenda-based biases affecting species representativeness in crop history research are apparent. This study also highlights the limited geographic diffusion of most crops and the potential for deeper historical perspectives on how crops become marginal- ized and ‘forgotten’

    Consistent patterns of common species across tropical tree communities

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    International audienceAbstract Trees structure the Earth’s most biodiverse ecosystem, tropical forests. The vast number of tree species presents a formidable challenge to understanding these forests, including their response to environmental change, as very little is known about most tropical tree species. A focus on the common species may circumvent this challenge. Here we investigate abundance patterns of common tree species using inventory data on 1,003,805 trees with trunk diameters of at least 10 cm across 1,568 locations 1–6 in closed-canopy, structurally intact old-growth tropical forests in Africa, Amazonia and Southeast Asia. We estimate that 2.2%, 2.2% and 2.3% of species comprise 50% of the tropical trees in these regions, respectively. Extrapolating across all closed-canopy tropical forests, we estimate that just 1,053 species comprise half of Earth’s 800 billion tropical trees with trunk diameters of at least 10 cm. Despite differing biogeographic, climatic and anthropogenic histories 7 , we find notably consistent patterns of common species and species abundance distributions across the continents. This suggests that fundamental mechanisms of tree community assembly may apply to all tropical forests. Resampling analyses show that the most common species are likely to belong to a manageable list of known species, enabling targeted efforts to understand their ecology. Although they do not detract from the importance of rare species, our results open new opportunities to understand the world’s most diverse forests, including modelling their response to environmental change, by focusing on the common species that constitute the majority of their trees

    Bright Opportunities for Atmospheric Characterization of Small Planets: Masses and Radii of K2-3 b, c, and d and GJ3470 b from Radial Velocity Measurements and Spitzer Transits

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    We report improved masses, radii, and densities for four planets in two bright M-dwarf systems, K2-3 and GJ3470, derived from a combination of new radial velocity and transit observations. Supplementing K2 photometry with follow-up Spitzer transit observations refined the transit ephemerides of K2-3 b, c, and d by over a factor of 10. We analyze ground-based photometry from the Evryscope and Fairborn Observatory to determine the characteristic stellar activity timescales for our Gaussian Process fit, including the stellar rotation period and activity region decay timescale. The stellar rotation signals for both stars are evident in the radial velocity data and is included in our fit using a Gaussian process trained on the photometry. We find the masses of K2-3 b, K2-3 c, and GJ3470 b to be 6.48{}-0.93+0.99, 2.14{}-1.04+1.08, and 12.58{}-1.28+1.31 M ⊕, respectively. K2-3 d was not significantly detected and has a 3σ upper limit of 2.80 M ⊕. These two systems are training cases for future TESS systems; due to the low planet densities (ρ < 3.7 g cm-3) and bright host stars (K < 9 mag), they are among the best candidates for transmission spectroscopy in order to characterize the atmospheric compositions of small planets

    Going With the Flow: Sedimentary Evolution of the Jezero Western Fan, Mars

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    International audienceSedimentary fans developed at the mouths of Martian valleys have been interpreted as the deposits of sustained surface water flow on early Mars building either fluvial fan systems or deltas into standing bodies of water [1]. Whilst much insight has been gleaned from orbital observations, it is only possible to constrain the character, relative timing and persistence of ancient aqueous activity on Mars through detailed on-the-ground interrogation of sedimentary successions built during fan growth. A prominent sedimentary fan deposit at the western margin of Jezero crater – the Western fan – has been interpreted from orbital data/observations to be a river delta that prograded into an ancient lake basin during the Late Noachian-Early Hesperian epochs on Mars (~3.6-3.8 Ga) [2]. The Western fan deposit forms a point-sourced depositional system developed at the mouth of Neretva Vallis, a valley system that is incised across the crater rim and has an extensive extra-crater catchment draining over diverse ancient geological units in Nili Planum [4]. The mechanism of crater rim breaching remains unconstrained. Between 2022 and 2023, the Mars 2020 Perseverance rover explored the Western fan, with the objective of characterizing its paleoenvironmental context and collecting a diverse suite of sedimentary rock samples for return to Earth via the Mars Sample Return mission. Perseverance has now completed her traverse across the Western fan having commenced in the distal downstream sectors exposed at the erosional front of the fan and then crossing across its upper exposed surface toward the fan apex region near the mouth of Neretva Vallis. This transect provides a unique window into a Martian sediment routing system at a time when climate conditions permitted the flow of surface water. In this contribution, we review the overall sedimentary architecture of the fan and develop a model for its evolution based on detailed mapping of lithofacies changes across the fan. A first-order synoptic overview is presented

    From TgO/GABA-AT, GABA, and T-263 Mutant to Conception of Toxoplasma

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    Toxoplasma gondii causes morbidity, mortality, and disseminates widely via cat sexual stages. Here, we find T. gondii ornithine aminotransferase (OAT) is conserved across phyla. We solve TgO/GABA-AT structures with bound inactivators at 1.55 Å and identify an inactivator selective for TgO/GABA-AT over human OAT and GABA-AT. However, abrogating TgO/GABA-AT genetically does not diminish replication, virulence, cyst-formation, or eliminate cat's oocyst shedding. Increased sporozoite/merozoite TgO/GABA-AT expression led to our study of a mutagenized clone with oocyst formation blocked, arresting after forming male and female gametes, with “Rosetta stone”-like mutations in genes expressed in merozoites. Mutations are similar to those in organisms from plants to mammals, causing defects in conception and zygote formation, affecting merozoite capacitation, pH/ionicity/sodium-GABA concentrations, drawing attention to cyclic AMP/PKA, and genes enhancing energy or substrate formation in TgO/GABA-AT-related-pathways. These candidates potentially influence merozoite's capacity to make gametes that fuse to become zygotes, thereby contaminating environments and causing disease

    Evaluating protein cross-linking as a therapeutic strategy to stabilize SOD1 variants in a mouse model of familial ALS.

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    Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS) cases. A shared effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers that seed toxic aggregates. Considerable research effort has been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but unfortunately, this has not yet resulted in a treatment. We hypothesized that cyclic thiosulfinate cross-linkers, which selectively target a rare, 2 cysteine-containing motif, can stabilize fALS-causing SOD1 variants in vivo. We created a library of chemically diverse cyclic thiosulfinates and determined structure-cross-linking-activity relationships. A pre-lead compound, "S-XL6," was selected based upon its cross-linking rate and drug-like properties. Co-crystallographic structure clearly establishes the binding of S-XL6 at Cys 111 bridging the monomers and stabilizing the SOD1 dimer. Biophysical studies reveal that the degree of stabilization afforded by S-XL6 (up to 24°C) is unprecedented for fALS, and to our knowledge, for any protein target of any kinetic stabilizer. Gene silencing and protein degrading therapeutic approaches require careful dose titration to balance the benefit of diminished fALS SOD1 expression with the toxic loss-of-enzymatic function. We show that S-XL6 does not share this liability because it rescues the activity of fALS SOD1 variants. No pharmacological agent has been proven to bind to SOD1 in vivo. Here, using a fALS mouse model, we demonstrate oral bioavailability; rapid engagement of SOD1G93A by S-XL6 that increases SOD1G93A's in vivo half-life; and that S-XL6 crosses the blood-brain barrier. S-XL6 demonstrated a degree of selectivity by avoiding off-target binding to plasma proteins. Taken together, our results indicate that cyclic thiosulfinate-mediated SOD1 stabilization should receive further attention as a potential therapeutic approach for fALS
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