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Dimerization of the thrombopoietin receptor (TpoR) is necessary for receptor activation and downstream signaling through activated Janus kinase 2. We have shown previously that different orientations of the transmembrane (TM) helices within a receptor dimer can lead to different signaling outputs. Here we addressed the structural basis of activation for receptor mutations S505N and W515K that induce myeloproliferative neoplasms. We show using in vivo bone marrow reconstitution experiments that ligand-independent activation of TpoR by TM asparagine (Asn) substitutions is proportional to the proximity of the mutation to the intracellular membrane surface. Solid-state NMR experiments on TM peptides indicate a progressive loss of helical structure in the juxtamembrane (JM) R/KWQFP motif with either proximity of Asn substitutions to the cytosolic boundary or mutation of W515 in the motif. Mutational studies in the TpoR cytosolic JM region show that the helical loss by itself can induce activation, but is localized to a maximum of 6 amino acids downstream of W515, the rest of the region until Box 1 requiring helicity for receptor function. The constitutive activation of TpoR mutants S505N and W515K can be inhibited by rotation of TM helices within the TpoR dimer, which also restores helicity around W515. Together these data allow us to develop a general model for activation and to explain the critical role of the JM W515 residue in the regulation of receptor activity.(Total manuscript without References and Figure Legends 6507 words, main text (without methods and materials):)

As I understand it, the central aim of the field of CSR is to reconcile (in the sense of “consilience”) methods and theories from the natural sciences with research on religion, which though defined in various ways, is usually understood as a universal human phenomenon. This does not necessarily mean religion is innate, but like all universal human phenomena, there will be an evolutionary story to tell about how it, or its constituent elements, came about. The stories are usually about the phenomena of religion writ-large, variously defined, rarely reaching the granularity to make claims about specific historical and cultural circumstances where religion is most relevant to agents. I challenge all scholars of religion to make their metaphysics explicit.

In 2013, a Lancet Infectious Diseases Commission described the state of antimicrobial resistance worldwide. Since then, greater awareness of the public health ramifications of antimicrobial resistance has led to national actions and global initiatives, including a resolution at the high-level meeting of the UN General Assembly in 2016. Progress in addressing this issue has ranged from a ban on irrational drug combinations in India to commitments to ban colistin as a growth promoter in animals, improve hospital infection control, and implement better antimicrobial stewardship. Funds have been mobilised, and regulatory barriers to new antibiotic development have been relaxed. These efforts have been episodic and uneven across countries, however. Sustained funding for antimicrobial resistance and globally harmonised targets to monitor progress are still urgently needed. Except for in a few leading countries, antimicrobial resistance has not captured the sustained focus of national leaders and country-level actors, including care providers.

Philadelphia-negative classical Myeloproliferative Neoplasms (MPNs), including Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF), are clonal hemopathies that emerge in the hematopoietic stem cell (HSC) compartment. MPN driver mutations are restricted to specific exons (14 and 12) of Janus kinase 2 (JAK2), thrombopoietin receptor (MPL/TPOR) and calreticulin (CALR) genes, are involved directly in clonal myeloproliferation and generate the MPN phenotype. As a result, an increased number of fully functional erythrocytes, platelets and leukocytes is observed in the peripheral blood. Nevertheless, the complexity and heterogeneity of MPN clinical phenotypes cannot be solely explained by the type of driver mutation. Other factors, such as additional somatic mutations affecting epigenetic regulators or spliceosomes components, mutant allele burdens and modifiers of signaling by driver mutants, clonal architecture and the order of mutation acquisition, signaling events that occur downstream of a driver mutation, the presence of specific germ-line variants, the interaction of the neoplastic clone with bone marrow microenvironment and chronic inflammation, all can modulate the disease phenotype, influence the MPN clinical course and therefore, might be useful therapeutic targets.

High-throughput sequencing (HTS) of the immunoglobulin heavy chain (IgH) locus is a recent very efficient technique to monitor minimal residual disease of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). It also reveals the sequences of clonal rearrangements, therefore, the multiclonal structure, of BCP-ALL. In this study, we performed IgH HTS on the diagnostic bone marrow of 105 children treated between 2004 and 2008 in Belgium for BCP-ALL in the European Organization for Research and Treatment of Cancer (EORTC)-58951 clinical trial. Patients were included irrespectively of their outcome. We described the patterns of clonal complexity at diagnosis and investigated its association with patients’ characteristics. Two indicators of clonal complexity were used, namely, the number of foster clones, described as clones with similar D-N2-J rearrangements but other V-rearrangement and N1-joining, and the maximum across all foster clones of the number of evolved clones from one foster clone. The maximum number of evolved clones was significantly higher in patients with t(12;21)/ETV6:RUNX1. A lower number of foster clones was associated with a higher risk group after prephase and t(12;21)/ETV6:RUNX1 genetic type. This study observes that clonal complexity as accessed by IgH HTS is linked to prognostic factors in childhood BCP-ALL, suggesting that it may be a useful diagnostic tool for BCP-ALL status and prognosis.

An approach to understanding religion that draws on both humanities and natural science but rejects approaches that employ simple monisms and radical dualisms. In Beyond Heaven and Earth, Gabriel Levy argues that collective religious narratives and beliefs are part of nature; they are the basis for the formation of the narratives and beliefs of individuals. Religion grows out of the universe, but to make sense of it we have to recognize the paradox that the universe is both mental and material (or neither). We need both humanities and natural science approaches to study religion and religious meaning, Levy contends, but we must also recognize the limits of these approaches. First, we must make the dominant metaphysics that undergird the various disciplines of science and humanities more explicit, and second, we must reject those versions of metaphysics that maintain simple monisms and radical dualisms. Bringing Donald Davidson's philosophy—a form of pragmatism known as anomalous monism—to bear on religion, Levy offers a blueprint for one way that the humanities and natural sciences can have a mutually respectful dialogue. Levy argues that in order to understand religions we have to take their semantic content seriously. We need to rethink such basic concepts as narrative fiction, information, agency, creativity, technology, and intimacy. In the course of his argument, Levy considers the relation between two closely related semantics, fiction and religion, and outlines a new approach to information. He then applies his theory to discrete cases: ancient texts, modern media, and intimacy.

During SARS-CoV-2 infection, the innate immune response can be inhibited or delayed, and the subsequent persistent viral replication can induce emergency signals that may culminate in a cytokine storm contributing to the severe evolution of COVID-19. Cytokines are key regulators of the immune response and virus clearance, and, as such, are linked to the—possibly altered—response to the SARS-CoV-2. They act via a family of more than 40 transmembrane receptors that are coupled to one or several of the 4 Janus kinases (JAKs) coded by the human genome, namely JAK1, JAK2, JAK3, and TYK2. Once activated, JAKs act on pathways for either survival, proliferation, differentiation, immune regulation or, in the case of type I interferons, antiviral and antiproliferative effects. Studies of graft-versus-host and systemic rheumatic diseases indicated that JAK inhibitors (JAKi) exert immunosuppressive effects that are non-redundant with those of corticotherapy. Therefore, they hold the potential to cut-off pathological reactions in COVID-19. Significant clinical experience already exists with several JAKi in COVID-19, such as baricitinib, ruxolitinib, tofacitinib, and nezulcitinib, which were suggested by a meta-analysis (Patoulias et al.) to exert a benefit in terms of risk reduction concerning major outcomes when added to standard of care in patients with COVID-19. Yet, only baricitinib is recommended in first line for severe COVID-19 treatment by the WHO, as it is the only JAKi that has proven efficient to reduce mortality in individual randomized clinical trials (RCT), especially the Adaptive COVID-19 Treatment Trial (ACTT-2) and COV-BARRIER phase 3 trials. As for secondary effects of JAKi treatment, the main caution with baricitinib consists in the induced immunosuppression as long-term side effects should not be an issue in patients treated for COVID-19.We discuss whether a class effect of JAKi may be emerging in COVID-19 treatment, although at the moment the convincing data are for baricitinib only. Given the key role of JAK1 in both type I IFN action and signaling by cytokines involved in pathogenic effects, establishing the precise timing of treatment will be very important in future trials, along with the control of viral replication by associating antiviral molecules.

Objectives: Optimal treatment of carbapenem-resistant Gram-negative bacteria (CR-GNB) infections is uncertain because of the lack of good-quality evidence and the limited effectiveness of available antibiotics. The aim of this survey was to investigate clinicians' prescribing strategies for treating CR-GNB infections worldwide. Methods: A 36-item questionnaire was developed addressing the following aspects of antibiotic prescribing: respondent's background, diagnostic and therapeutic availability, preferred antibiotic strategies and rationale for selecting combination therapy. Prescribers were recruited following the snowball sampling approach, and a post-stratification correction with inverse proportional weights was used to adjust the sample's representativeness. Results: A total of 1012 respondents from 95 countries participated in the survey. Overall, 298 (30%) of the respondents had local guidelines for treating CR-GNB at their facility and 702 (71%) had access to Infectious Diseases consultation, with significant discrepancies according to country economic status: 85% (390/502) in high-income countries versus 59% (194/283) in upper-medium-income countries and 30% (118/196) in lower-middle-income countries/lower-income-countries). Targeted regimens varied widely, ranging from 40 regimens for CR-Acinetobacter spp. to more than 100 regimens for CR-Enterobacteriaceae. Although the majority of respondents acknowledged the lack of evidence behind this choice, dual combination was the preferred treatment scheme and carbapenem-polymyxin was the most prescribed regimen, irrespective of pathogen and infection source. Respondents noticeably disagreed around the meaning of ‘combination therapy’ with 20% (150/783) indicating the simple addition of multiple compounds, 42% (321/783) requiring the presence of in vitro activity and 38% (290/783) requiring in vitro synergism. Conclusions: Management of CR-GNB infections is far from being standardized. Strategic public health focused randomized controlled trials are urgently required to inform evidence-based treatment guidelines.

BACKGROUND: Variation in the approaches taken to contain the SARS-CoV-2 (COVID-19) pandemic at country level has been shaped by economic and political considerations, technical capacity, and assumptions about public behaviours. To address the limited application of learning from previous pandemics, this study aimed to analyse perceived facilitators and inhibitors during the pandemic and to inform the development of an assessment tool for pandemic response planning. METHODS: A cross-sectional electronic survey of health and non-health care professionals (5 May - 5 June 2020) in six languages, with respondents recruited via email, social media and website posting. Participants were asked to score inhibitors (-10 to 0) or facilitators (0 to +10) impacting country response to COVID-19 from the following domains - Political, Economic, Sociological, Technological, Ecological, Legislative, and wider Industry (the PESTELI framework). Participants were then asked to explain their responses using free text. Descriptive and thematic analysis was followed by triangulation with the literature and expert validation to develop the assessment tool, which was then compared with four existing pandemic planning frameworks. RESULTS: 928 respondents from 66 countries (57% health care professionals) participated. Political and economic influences were consistently perceived as powerful negative forces and technology as a facilitator across high- and low-income countries. The 103-item tool developed for guiding rapid situational assessment for pandemic planning is comprehensive when compared to existing tools and highlights the interconnectedness of the 7 domains. CONCLUSIONS: The tool developed and proposed addresses the problems associated with decision making in disciplinary silos and offers a means to refine future use of epidemic modelling.

Additional material: Online Supplementary Document available at http://jogh.org/documents/2021/jogh-11-05011-s001.pdf . Copyright © 2021 The Author(s). Background: Variation in the approaches taken to contain the SARS-CoV-2 (COVID-19) pandemic at country level has been shaped by economic and political considerations, technical capacity, and assumptions about public behaviours. To address the limited application of learning from previous pandemics, this study aimed to analyse perceived facilitators and inhibitors during the pandemic and to inform the development of an assessment tool for pandemic response planning. Methods A cross-sectional electronic survey of health and non-health care professionals (5 May - 5 June 2020) in six languages, with respondents recruited via email, social media and website posting. Participants were asked to score inhibitors (−10 to 0) or facilitators (0 to +10) impacting country response to COVID-19 from the following domains - Political, Economic, Sociological, Technological, Ecological, Legislative, and wider Industry (the PESTELI framework). Participants were then asked to explain their responses using free text. Descriptive and thematic analysis was followed by triangulation with the literature and expert validation to develop the assessment tool, which was then compared with four existing pandemic planning frameworks. Results 928 respondents from 66 countries (57% health care professionals) participated. Political and economic influences were consistently perceived as powerful negative forces and technology as a facilitator across high- and low-income countries. The 103-item tool developed for guiding rapid situational assessment for pandemic planning is comprehensive when compared to existing tools and highlights the interconnectedness of the 7 domains. Conclusions The tool developed and proposed addresses the problems associated with decision making in disciplinary silos and offers a means to refine future use of epidemic modelling. This study did not receive any external funding.

Background Point prevalence surveys (PPSs) on antibiotic use are useful for understanding different aspects related to prescription patterns in hospitals. Methods An adaptation of the WHO methodology for a PPS on antibiotic use was applied. Hospital wards were divided into medical (MED), surgical (SUR), ICUs, gynaecology and obstetrics (GO), high-risk (HR) and mixed wards (MIX). A web application (RedCap©) through a mobile device was used for data collection. Results Between December 2018 and August 2019, 5444 patients in 33 hospitals in five countries were included (10 hospitals in Cuba, 7 in Paraguay, 6 in El Salvador, 5 in Mexico and 5 in Peru). Of these patients, 54.6% received at least one antibiotic, with variations between and within hospitals and countries. Antibiotics were more frequently used in ICUs (67.2%), SUR (64.5%) and MED wards (54.2%), with 51.2% of antibiotics prescribed for community-acquired infections (CAIs), 22.9% for healthcare-associated infections (HAIs), 11.1% for surgical prophylaxis and 6.1% for unknown reasons. Adherence to guidelines was observed in 68.6% of cases (72.8% for CAIs, 72.4% for HAIs and 44.3% for prophylaxis). Third-generation cephalosporins were the class of antibiotics most frequently used (26.8%), followed by carbapenems (10.3%) and fluoroquinolones (8%). Targeted treatments were achieved in 17.3% of cases. Conclusions Antibiotic use was generally higher than that published in other studies. There is an urgent need to promote and strengthen the antimicrobial stewardship programmes in Latin America.

Metatarsophalangeal arthritis of the first ray of the foot, also known as hallux rigidus, is an invalidating cause of walking that is still underestimated. It is associated to a local deformation of the first ray with a limitation of the dorsal mobilization of the joint, affecting thus the propulsion of the foot. Several stages of the disease exist, and symptoms as well as the treatment will depend on the moment of the consultation. In this paper, we present the different clinical pictures and adapted treatments according to the stage of the disease, and we share our results of a new modality of surgery that conserves the articular mobility of the joint.L’arthrose métatarsophalangienne du premier rayon du pied, connue également sous le nom de « hallux rigidus », est une pathologie invalidante de la marche encore sous-estimée. Elle est associée à une déformation localisée du premier rayon et à une limitation de la flexion dorsale au niveau de l’articulation, affectant ainsi la propulsion. Plusieurs stades de cette maladie existent, et les symptômes ainsi que leurs traitements dépendront du moment de consultation. Dans cet article, nous présentons les différents symptômes et traitements de cette arthrose, adaptés selon le stade en partageant notre expérience avec les nouveautés technologiques conservatrices du mouvement articulaire et leur résultat à moyen terme.

Congenital amegakaryocytic thrombocytopenia (CAMT) is a severe inherited thrombocytopenia due to loss-of-function mutations affecting the thrombopoietin (TPO) receptor, MPL. Here, we report a new homozygous MPL variant responsible for CAMT in 1 consanguineous family. The propositus and her sister presented with severe thrombocytopenia associated with mild anemia. Next-generation sequencing revealed the presence of a homozygous MPLR464G mutation resulting in a weak cell-surface expression of the receptor in platelets. In cell lines, we observed a defect in MPLR464G maturation associated with its retention in the endoplasmic reticulum. The low cell-surface expression of MPLR464G induced very limited signaling with TPO stimulation, leading to survival and reduced proliferation of cells. Overexpression of a myeloproliferative neoplasm–associated calreticulin (CALR) mutant did not rescue trafficking of MPLR464G to the cell surface and did not induce constitutive signaling. However, it unexpectedly restored a normal response to eltrombopag (ELT), but not to TPO. This effect was only partially mimicked by the purified recombinant CALR mutant protein. Finally, the endogenous CALR mutant was able to restore the megakaryocyte differentiation of patient CD34+ cells carrying MPLR464G in response to ELT.

BackgroundHealthcare professionals are increasingly expected to lead antimicrobial stewardship (AMS) initiatives. This role in complex healthcare environments requires specialized training.ObjectivesLittle is known about the types of AMS training programmes available to clinicians seeking to play a lead role in AMS. We aimed to identify clinicians’ awareness of AMS training programmes, characteristics of AMS training programmes available and potential barriers to participation.MethodsAMS training programmes available were identified by members of the ESCMID Study Group for Antimicrobial Stewardship (ESGAP) via an online survey and through an online search in 2018. Individual training programme course coordinators were then contacted (September–October 2018) for data on the target audience(s), methods of delivery, intended outcomes and potential barriers to accessing the training programme.ResultsA total of 166/250 ESGAP members (66%) responded to the survey, nominating 48 unique AMS training programmes. An additional 32 training programmes were identified through an online search. AMS training programmes were from around the world. Less than half (44.4%) of respondents were aware of one or more AMS training programmes available, with pharmacists more aware compared with medical doctors and other professionals (73% versus 46% and 25%, respectively). AMS training programmes were most commonly delivered online (59%) and aimed at medical doctors (46%). Training costs and a lack of recognition by health professional societies were the most frequently cited barriers to participation in AMS training programmes.ConclusionsThe development of a systematic inventory of AMS training programmes around the globe identifies opportunities and limitations to current training available. Improving access and increasing awareness amongst target participants will support improved education in AMS.

Background Inappropriate antibiotic use represents a major global threat. Sepsis and bacterial lower respiratory tract infections (LRTIs) have been linked to antimicrobial resistance, carrying important consequences for patients and health systems. Procalcitonin-guided algorithms may represent helpful tools to reduce antibiotic overuse but the financial burden is unclear. The aim of this study was to estimate the healthcare and budget impact in Argentina of using procalcitonin-guided algorithms to guide antibiotic prescription. Methods A decision tree was used to model health and cost outcomes for the Argentinean health system, over a one-year duration. Patients with suspected sepsis in the intensive care unit and hospitalized patients with LRTI were included. Model parameters were obtained from a focused, non-systematic, local and international bibliographic search, and validated by a panel of local experts. Deterministic and probabilistic sensitivity analyses were performed to analyze the uncertainty of parameters. Results The model predicted that using procalcitonin-guided algorithms would result in 734.5 [95% confidence interval (CI): 1,105.2;438.8] thousand fewer antibiotic treatment days, 7.9 [95% CI: 18.5;8.5] thousand antibiotic-resistant cases avoided, and 5.1 [95% CI: 6.7;4.2] thousand fewer Clostridioides difficile cases. In total, this would save $422.4 US dollars (USD) [95% CI: $935;$267] per patient per year, meaning cost savings of $83.0 [95% CI: $183.6;$57.7] million USD for the entire health system and $0.4 [95% CI: $0.9;$0.3] million USD for a healthcare provider with 1,000 cases per year of sepsis and LRTI patients. The sensitivity analysis showed that the probability of cost-saving for the sepsis patient group was lower than for the LRTI patient group (85% vs. 100%). Conclusions Healthcare and financial benefits can be obtained by implementing procalcitonin-guided algorithms in Argentina. Although we found results to be robust on an aggregate level, some caution must be used when focusing only on sepsis patients in the intensive care unit.

Objectives/Purpose The costs attributable to antimicrobial resistance (AMR) remain theoretical and largely unspecified. Current figures fail to capture the full health and economic burden caused by AMR across human, animal, and environmental health; historically many studies have considered only direct costs associated with human infection from a hospital perspective, primarily from high-income countries. The Global Antimicrobial Resistance Platform for ONE-Burden Estimates (GAP-ON€) network has developed a framework to help guide AMR costing exercises in any part of the world as a first step towards more comprehensive analyses for comparing AMR interventions at the local level as well as more harmonized analyses for quantifying the full economic burden attributable to AMR at the global level.Methods GAP-ON€ (funded under the JPIAMR 8th call (Virtual Research Institute) is composed of 19 international networks and institutions active in the field of AMR. For this project, the Network operated by means of Delphi rounds, teleconferences and face-to-face meetings. The resulting costing framework takes a bottom-up approach to incorporate all relevant costs imposed by an AMR bacterial microbe in a patient, in an animal, or in the environment up through to the societal level. Results The framework itemizes the epidemiological data as well as the direct and indirect cost components needed to build a realistic cost picture for AMR. While the framework lists a large number of relevant pathogens for which this framework could be used to explore the costs, the framework is sufficiently generic to facilitate the costing of other resistant pathogens, including those of other aetiologies. Conclusion In order to conduct cost-effectiveness analyses to choose amongst different AMR-related interventions at local level, the costing of AMR should be done according to local epidemiological priorities and local health service norms. Yet the use of a common framework across settings allows for the results of such studies to contribute to cumulative estimates that can serve as the basis of broader policy decisions at the international level such as how to steer R&D funding and how to prioritize AMR amongst other issues. Indeed, it is only by building a realistic cost picture that we can make informed decisions on how best to tackle major health threats.

To examine published antimicrobial stewardship (AMS) initiatives in hospitals in Latin America and the Caribbean (LAC) in order to characterize AMS terminology usage, geotemporality, and elements of structure (human resources), process (interventions), and outcomes, and to set priority areas for improving AMS reporting.This was a scoping review that searched PubMed, LILACS, EMBASE, and 12 other databases, along with a manual search for academic and grey literature to identify documents on AMS initiatives in hospitals in 33 countries of LAC, up to August 2019. Keywords included 'antibiotic' or 'antimicrobial' AND 'stewardship, policy, strategies, management, control, rational use, appropriate use, surveillance, or interventions' and 33 country names.Selected articles totalled 147 studies published in 1985 - 2019; of those, 22% used 'antimicrobial stewardship' in the title. Eighteen countries published AMS hospital initiatives, one-half of which were implemented in capital cities. Brazil, Argentina, Colombia, Cuba, Mexico, and Chile, in descending frequency, made up59% of published initiatives. Educational interventions were the most frequently reported, followed by persuasive and restrictive strategies. Antimicrobial consumption was the most common outcome measure reported. About one-third of the studies (35%) referred to baseline measures-only in preparation for AMS interventions. Fifty-nine studies from 6 countries reported AMS comprehensively, using structure, process, and outcome (SPO) elements.Published hospital AMS initiatives have increased over time and have expanded across LAC. However, more programs need to be developed. Complete reporting of SPO elements is imperative to evaluating and replicating AMS actions.Examinar las iniciativas publicadas sobre optimización del uso de antimicrobianos (OUA) en hospitales de América Latina y el Caribe para caracterizar el uso de la terminología, la geotemporalidad y algunos elementos de la estructura (recursos humanos), el proceso (intervenciones) y los resultados, así como para establecer las áreas prioritarias para mejorar la información sobre este tema.En esta revisión exploratoria se realizaron búsquedas en PubMed, LILACS, Embase y otras doce bases de datos, además de una búsqueda manual de la bibliografía académica y gris, con el fin de encontrar documentos acerca de las iniciativas de optimización del uso de antimicrobianos en hospitales de 33 países de América Latina y el Caribe hasta agosto del 2019. Algunas de las palabras clave fueron “antibiótico” o “antimicrobiano” Y “rectoría”, “política”, “estrategias”, “gestión”, “control”, “uso racional”, “uso apropiado”, “vigilancia” o “intervenciones”, además de los nombres de los 33 países.Los artículos seleccionados sumaron 147 estudios publicados entre 1985 y el 2019, de los que en un 22 % se mencionó la optimización del uso de antimicrobianos (‘antimicrobial stewardship’) en su título. Dieciocho países publicaron iniciativas de optimización del uso de antimicrobianos para hospitales, la mitad de las cuales se ejecutaron en sus ciudades capitales. Brasil, Argentina, Colombia, Cuba, México y Chile, en orden descendente según la frecuencia, constituyeron más del 59% de las iniciativas publicadas. Las intervenciones educativas fueron las que se informaron con mayor frecuencia, seguidas por las estrategias persuasivas y restrictivas. La medida de resultado notificada más comúnmente fue el consumo de antimicrobianos. Cerca de un tercio de los estudios (35%) se refirió únicamente a las mediciones de base en preparación para las intervenciones de optimización del uso de antimicrobianos. Cincuenta y nueve estudios de seis países informaron exhaustivamente sobre las iniciativas de optimización del uso de antimicrobianos mediante elementos relativos a la estructura, el proceso y los resultados (EPR).Las iniciativas publicadas sobre la optimización del uso de antimicrobianos en los hospitales han aumentado con el transcurso del tiempo y se han ampliado en América Latina y el Caribe. Sin embargo, se necesitan más programas. Es esencial suministrar información completa de los elementos relativos a la EPR para evaluar y replicar las medidas de optimización del uso de antimicrobianos.Examinar iniciativas publicadas sobre a otimização do uso de antimicrobianos em hospitais da América Latina e Caribe (ALC), caracterizar o uso da terminologia sobre iniciativas de otimização do uso de antimicrobianos, geotemporalidade e elementos das estruturas (recursos humanos), processos (intervenções) e resultados, bem como estabelecer áreas prioritárias para melhorar a publicação de estudos sobre iniciativas de otimização do uso de antimicrobianos.Realizamos uma revisão exploratória pesquisando as bases de dados PubMed, LILACS, EMBASE e outras 12, juntamente com uma pesquisa manual da literatura acadêmica e cinzenta para identificar artigos sobre iniciativas de otimização do uso de antimicrobianos em hospitais de 33 países da ALC, até agosto de 2019. Os termos de busca foram ‘antibiótico’ ou ‘antimicrobiano’ E ‘gestão, políticas, estratégias, gerenciamento, controle, uso racional, uso apropriado, vigilância ou intervenções’, bem como os nomes de 33 países.Os artigos selecionados totalizaram 147 estudos publicados entre 1985 e 2019; desses, 22% utilizaram a expressão ‘iniciativas de otimização do uso de antimicrobianos’ (‘As iniciativas publicadas sobre a otimização do uso de antimicrobianos em hospitais têm aumentado ao longo do tempo, expandindo-se em toda a ALC. No entanto, é preciso desenvolver mais programas. A descrição completa de elementos de EPR é fundamental para avaliar e reproduzir as ações de otimização do uso de antimicrobianos.

Introduction: Carbapenemases are β-lactamases able to hydrolyze a wide range of β-lactam antibiotics, including carbapenems. Carbapenemase production in Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter spp., with and without the co-expression of other β-lactamases is a serious public health threat. Carbapenemases belong to three main classes according to the Ambler classification: class A, class B, and class D. Areas covered: Carbapenemase-bearing pathogens are endemic in Latin America. In this review, we update the status of carbapenemases in Latin America and the Caribbean. Expert opinion: Understanding the current epidemiology of carbapenemases in Latin America and the Caribbean is of critical importance to improve infection control policies limiting the dissemination of multi-drug-resistant pathogens and in implementing appropriate antimicrobial therapy.

Antimicrobial stewardship (AMS) is a set of coordinated strategies to improve the use of antimicrobials, to enhance patient outcomes, reduce antimicrobial resistance, and decrease unnecessary costs. The pioneer years of AMS were restricted to high-income countries (HIC), where overconsumption of antibiotics was associated with emergence of multidrug-resistant (MDR) bacteria. AMS in low- and middle-income countries (LMIC) is also necessary. However, programs effective in HIC may not perform as well in LMIC, because (i) While decreased consumption of antibiotics may be an appropriate target in overconsuming HIC, this may be dangerous in LMIC, where many patients die from the lack of access to antibiotics; (ii) although AMS programs in HIC can be designed and monitored through laboratory surveillance of resistance, surveillance programs are not available in many LMIC; (iii) the heterogeneity of health care systems implies that AMS programs must be carefully contextualized. Despite the need to individually tailor AMS programs in LMIC, international collaborations remain highly valuable, through the dissemination of high-quality documents and educational material, that may be shared, adapted where needed, and adopted worldwide. This process, facilitated by modern communication tools, combines many benefits, including: (i) saving time, a precious dimension for health care workers, by avoiding the duplication of similar works in different settings; (ii) taking advantage of colleagues skills, and initiatives, through open access to the work performed in other parts of the world; (iii) sharing experiences, so that we all learn from each others' successes and failures.

Objectives/PurposeThe costs attributable to antimicrobial resistance (AMR) across human, animal, and environmental health remain theoretical and largely unspecified. Current figures fail to capture the full health and economic burden caused by AMR; historically many studies have considered only direct costs associated with human infection from a hospital perspective, primarily from high-income countries. The Global Antimicrobial Resistance Platform for ONE-Burden Estimates (GAP-ON€) network aimed to develop a global, One Health AMR Cost Framework, that can be used by countries, regions, and other entities to quantify the economic burden attributable to AMR.MethodsGAP-ON€ (funded under the JPIAMR 8th call (Virtual Research Institute) is composed of 19 international networks and institutions active in the field of AMR. It operated by means of Delphi rounds, teleconferences (TCs) and face-to-face (F2F) meetings. It assumes a bottom-up cost estimate, at the National level, with a global scope across all One Health Areas.ResultsThe resulting framework consists of the epidemiological data and the direct and indirect cost components, linked by the likelihood of each AMR-related health state that imposes such costs, across all One Health Areas for a large number of relevant pathogens. It represents a first step towards more comprehensive analyses for comparing cost-effectiveness of AMR interventions at the local level as well as more harmonised analyses at the global level.ConclusionThis is the first full AMR costing framework to be developed for bacterial pathogens in human and animal health and the environment. It aims to provide guidance on the data items necessary to calculate AMR costs in a global, One Health perspective to facilitate harmonized, full economic analyses. It is only through building a realistic cost picture that we can make informed decisions about potential strategies and political priorities.

Mutations in the MPL gene encoding the human thrombopoietin receptor (TpoR) drive sporadic and familial essential thrombocythemias (ETs). We identified 2 ET patients harboring double mutations in cis in MPL, namely, L498W-H499C and H499Y-S505N. Using biochemical and signaling assays along with partial saturation mutagenesis, we showed that L498W is an activating mutation potentiated by H499C and that H499C and H499Y enhance the activity of the canonical S505N mutation. L498W and H499C can activate a truncated TpoR mutant, which lacks the extracellular domain, indicating these mutations act on the transmembrane (TM) cytosolic domain. Using a protein complementation assay, we showed that L498W and H499C strongly drive dimerization of TpoR. Activation by tryptophan substitution is exquisitely specific for position 498. Using structure-guided mutagenesis, we identified upstream amino acid W491 as a key residue required for activation by L498W or canonical activating mutations such as S505N and W515K, as well as by eltrombopag. Structural data point to a common dimerization and activation path for TpoR via its TM domain that is shared between the small-molecule agonist eltrombopag and canonical and novel activating TpoR mutations that all depend on W491, a potentially accessible extracellular residue that could become a target for therapeutic intervention.

Background: Variation in the approaches taken to contain the SARS-CoV-2 (COVID-19) pandemic at country level has been shaped by economic and political considerations, technical capacity, and assumptions about public behaviours. To address the limited application of learning from previous pandemics, this study aimed to analyse perceived facilitators and inhibitors during the pandemic and to inform the development of an assessment tool for pandemic response planning. Methods: A cross-sectional electronic survey of health and non-healthcare professionals (5 May - 5 June 2020) in six languages, with respondents recruited via email, social media and website posting. Participants were asked to score inhibitors (-10 to 0) or facilitators (0 to +10) impacting country response to COVID-19 from the following domains – Political, Economic, Sociological, Technological, Ecological, Legislative, and wider Industry (the PESTELI framework). Participants were then asked to explain their responses using free text. Descriptive and thematic analysis was followed by triangulation with the literature and expert validation to develop the assessment tool, which was then compared with four existing pandemic planning frameworks. Findings: 928 respondents from 66 countries (57% healthcare professionals) participated. Political and economic influences were consistently perceived as powerful negative forces and technology as a facilitator across high- and low-income countries. The 103-item tool developed for guiding rapid situational assessment for pandemic planning is comprehensive when compared to existing tools and highlights the interconnectedness of the 7 domains. Interpretation: The tool developed and proposed addresses the problems associated with decision making in disciplinary silos and offers a means to refine future use of epidemic modelling. Funding Statement: This study did not receive any external funding. Declaration of Interests: None to declare. Ethics Approval Statement: The study was approved by the Joint Research Compliance Office, Imperial College London (ICREC reference: 20IC5947).

International audience; Antimicrobial stewardship (AMS) is a set of coordinated strategies to improve the use of antimicrobials, to enhance patient outcomes, reduce antimicrobial resistance, and decrease unnecessary costs. The pioneer years of AMS were restricted to high-income countries (HIC), where overconsumption of antibiotics was associated with emergence of multidrug-resistant (MDR) bacteria. AMS in low- and middle-income countries (LMIC) is also necessary. However, programs effective in HIC may not perform as well in LMIC, because (i) While decreased consumption of antibiotics may be an appropriate target in overconsuming HIC, this may be dangerous in LMIC, where many patients die from the lack of access to antibiotics; (ii) although AMS programs in HIC can be designed and monitored through laboratory surveillance of resistance, surveillance programs are not available in many LMIC; (iii) the heterogeneity of health care systems implies that AMS programs must be carefully contextualized. Despite the need to individually tailor AMS programs in LMIC, international collaborations remain highly valuable, through the dissemination of high-quality documents and educational material, that may be shared, adapted where needed, and adopted worldwide. This process, facilitated by modern communication tools, combines many benefits, including: (i) saving time, a precious dimension for health care workers, by avoiding the duplication of similar works in different settings; (ii) taking advantage of colleagues skills, and initiatives, through open access to the work performed in other parts of the world; (iii) sharing experiences, so that we all learn from each others' successes and failures.

[Objectives/purpose] The costs attributable to antimicrobial resistance (AMR) remain theoretical and largely unspecified. Current figures fail to capture the full health and economic burden caused by AMR across human, animal, and environmental health; historically many studies have considered only direct costs associated with human infection from a hospital perspective, primarily from high-income countries. The Global Antimicrobial Resistance Platform for ONE-Burden Estimates (GAP-ON€) network has developed a framework to help guide AMR costing exercises in any part of the world as a first step towards more comprehensive analyses for comparing AMR interventions at the local level as well as more harmonized analyses for quantifying the full economic burden attributable to AMR at the global level., [Methods] GAP-ON€ (funded under the JPIAMR 8th call (Virtual Research Institute) is composed of 19 international networks and institutions active in the field of AMR. For this project, the Network operated by means of Delphi rounds, teleconferences and face-to-face meetings. The resulting costing framework takes a bottom-up approach to incorporate all relevant costs imposed by an AMR bacterial microbe in a patient, in an animal, or in the environment up through to the societal level., [Results] The framework itemizes the epidemiological data as well as the direct and indirect cost components needed to build a realistic cost picture for AMR. While the framework lists a large number of relevant pathogens for which this framework could be used to explore the costs, the framework is sufficiently generic to facilitate the costing of other resistant pathogens, including those of other aetiologies., [Conclusion] In order to conduct cost-effectiveness analyses to choose amongst different AMR-related interventions at local level, the costing of AMR should be done according to local epidemiological priorities and local health service norms. Yet the use of a common framework across settings allows for the results of such studies to contribute to cumulative estimates that can serve as the basis of broader policy decisions at the international level such as how to steer R&D funding and how to prioritize AMR amongst other issues. Indeed, it is only by building a realistic cost picture that we can make informed decisions on how best to tackle major health threats., The creation of the GAP-ONE Network was supported under the framework of the Joint Programming Initiative on Antimicrobial Resistance and funded by the Italian Ministry of Health, within the JPIAMR 8th call, Virtual Research Initiative, 2018.

Sclerosing epithelioid fibrosarcoma (SEF) is a rare, malignant fibroblastic neoplasm, morphologically composed of cords, nests or sheets of monotonous epithelioid cells within a collagenous matrix. It has been recently characterized by recurrent pathogenic EWS-CREB3L1/2 or FUS-CREB3L2 fusions and common MUC4 protein expression by immunohistochemistry. Typically SEF occur in middle-aged adults and rarely have been reported within the abdominal cavity. Here we report an 18-year-old man with intraabdominal tumor and multiple disseminated liver metastases, presenting pure SEF histologic and immunophenotypic features. Fluorescence in situ hybridization analysis showed unbalanced rearrangement of Ewing sarcoma breakpoint region 1 (EWSR1) gene. Genomic profiling by array CGH, followed by RT-PCR and sequencing analysis, revealed a previously not reported EWSR1 translocation partner, cAMP-responsive element-binding protein 3-like 3 (CREB3L3). The novel EWSR1-CREB3L3 fusion further extends the range of fusion types involving EWSR1 that are characteristic for SEF.

Religious rituals are found all over the world. Some cultures engage in extreme religious rituals in which individuals take on forms of bodily harm to demonstrate their devotion. Such rituals entail excessive costs in terms of physical pain and effort, but the equivalent societal benefits remain unclear. The field experiment reported here examined the interplay between extreme rituals and moral behavior. Using a die-roll task to measure honest behavior, we tested whether engaging or observing others engaging in extreme ritual activities affects subsequent moral behavior. Strikingly, the results showed that extreme rituals promote moral behavior among ritual observers, but not among ritual performers. The discussion centres on the moral effects of rituals within the broader social context in which they occur. Extreme religious rituals appear to have a moral cleansing effect on the numerous individuals observing the rituals, which may imply that these rituals evolved to advance and maintain moral societies.

Camille Wingo, Pictures Making Beliefs: A Cognitive Technological Model for Ritual Efficacy (Durham, NC: Carolina Academic Press, 2012), 238 pp. $30.00 (pbk). ISBN: 978-1-59460-973-2.

Background The World Health Organization Essential Medicines List (WHO-EML) includes ‘access’ antibiotics, judged essential to treat common infections. The European Society of Clinical Microbiology and Infectious Diseases Study Group for Antimicrobial Stewardship defined a list of ‘forgotten’ antibiotics, some old and often off-patent antibiotics, which have particular value for specific indications. Objective To investigate which WHO-EML ‘access’ and ‘forgotten’ antibiotics are approved at national level in a sample of low- to middle-income countries (LMICs). Methods The Scientific Committee used a consensus procedure to select 26 WHO-EML ‘access’ and 15 ‘forgotten’ antibiotics. Paediatric formulations were explored for 14 antibiotics. An internet-based questionnaire was circulated to 40 LMIC representatives. Antibiotics were defined as approved if an official drug regulatory agency and/or the national ministry of health licensed their use, making them, at least theoretically, available on the market. Results Twenty-eight LMICs (11 in Africa, 11 in Asia and six in America) were surveyed. Nine WHO-EML ‘access’ antibiotics (amoxicillin, ampicillin, benzylpenicillin, ceftriaxone, clarithromycin, ciprofloxacin, doxycycline, gentamicin and metronidazole) were approved in all countries, and all 26 ‘access’ antibiotics were approved in more than two-thirds of countries. Among the 15 ‘forgotten’ antibiotics, only one was approved in more than two-thirds of countries. The median number of approved antibiotics per country was 30 (interquartile range 23–35). Six of 14 paediatric formulations (amoxicillin, amoxicillin-clavulanic acid, oral antistaphylococcal penicillin, cotrimoxazole, erythromycin and metronidazole) were approved in more than two-thirds of countries. Conclusions WHO-EML ‘access’ antibiotics and the most frequently used formulations for paediatrics were approved in the vast majority of the 28 surveyed LMICs. This was not the case for many of the ‘forgotten’ antibiotics, despite their important role, particularly in areas with high prevalence of multi-drug-resistant bacteria.

Objectives: With increasing global interest in hospital antimicrobial stewardship (AMS) programmes, there is a strong demand for core elements of AMS to be clearly defined on the basis of principles of effectiveness and affordability. To date, efforts to identify such core elements have been limited to Europe, Australia, and North America. The aim of this study was to develop a set of core elements and their related checklist items for AMS programmes that should be present in all hospitals worldwide, regardless of resource availability. Methods: A literature review was performed by searching Medline and relevant websites to retrieve a list of core elements and items that could have global relevance. These core elements and items were evaluated by an international group of AMS experts using a structured modified Delphi consensus procedure, using two-phased online in-depth questionnaires. Results: The literature review identified seven core elements and their related 29 checklist items from 48 references. Fifteen experts from 13 countries in six continents participated in the consensus procedure. Ultimately, all seven core elements were retained, as well as 28 of the initial checklist items plus one that was newly suggested, all with >= 80% agreement; 20 elements and items were rephrased. Conclusions: This consensus on core elements for hospital AMS programmes is relevant to both high- and low-to-middle-income countries and could facilitate the development of national AMS stewardship guidelines and adoption by healthcare settings worldwide. (C) 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Driver mutations occur in Janus kinase 2 (JAK2), thrombopoietin receptor (MPL), and calreticulin (CALR) in BCR-ABL1 negative myeloproliferative neoplasms (MPNs). From mutations leading to one amino acid substitution in JAK2 or MPL, to frameshift mutations in CALR resulting in a protein with a different C-terminus, all the mutated proteins lead to pathologic and persistent JAK2-STAT5 activation. The most prevalent mutation, JAK2 V617F, is associated with the 3 entities polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), while CALR and MPL mutations are associated only with ET and MF. Triple negative ET and MF patients may harbor noncanonical mutations in JAK2 or MPL. One major fundamental question is whether the conformations of JAK2 V617F, MPL W515K/L/A, or CALR mutants differ from those of their wild type counterparts so that a specific treatment could target the clone carrying the mutated driver and spare physiological hematopoiesis. Of great interest, a set of epigenetic mutations can co-exist with the phenotypic driver mutations in 35%–40% of MPNs. These epigenetic mutations, such as TET2, EZH2, ASXL1, or DNMT3A mutations, promote clonal hematopoiesis and increased fitness of aged hematopoietic stem cells in both clonal hematopoiesis of indeterminate potential (CHIP) and MPNs. Importantly, the main MPN driver mutation JAK2 V617F is also associated with CHIP. Accumulation of several epigenetic and splicing mutations favors progression of MPNs to secondary acute myeloid leukemia. Another major fundamental question is how epigenetic rewiring due to these mutations interacts with persistent JAK2-STAT5 signaling. Answers to these questions are required for better therapeutic interventions aimed at preventing progression of ET and PV to MF, and transformation of these MPNs in secondary acute myeloid leukemia.

Social and labour movements need a coherent critique of science and technology, it was argued at a meeting on “Radical Science and Alternative Technology”, held in London on 11 April 2015. On a pra...

Dear Editor, Myeloproliferative neoplasms (MPNs) are rare diseases in children [1] when compared to adults [2]. Targeted sequencing revealed differences in the mutational landscape of pediatric and adult MPNs [1]. Children exhibit a lower frequency of mutations in the MPN driver genes JAK2, MPL, and CALR, and a much higher proportion of children exhibit no mutation among the 104 classically involved genes; these children exhibiting a trend towards essential thrombocythemia (ET) [1]. We were surprised to read about an activating thrombopoietin receptor (TpoR/Mpl) S505A transmembrane domain (TM) mutation in childhood hereditary thrombocytosis (HT) and ET [3–5]. [...]

Cranial radiotherapy in children has detrimental effects on cognition, mood, and social competence in young cancer survivors. Treatments harnessing hippocampal neurogenesis are currently of great relevance in this context. Lithium, a well-known mood stabilizer, has both neuroprotective, pro-neurogenic as well as antitumor effects, and in the current study we introduced lithium treatment 4 weeks after irradiation. Female mice received a single 4 Gy whole-brain radiation dose on postnatal day (PND) 21 and were randomized to 0.24% Li2CO3 chow or normal chow from PND 49 to 77. Hippocampal neurogenesis was assessed on PND 77, 91, and 105. We found that lithium treatment had a pro-proliferative effect on neural progenitors, but neuronal integration occurred only after it was discontinued. Also, the treatment ameliorated deficits in spatial learning and memory retention observed in irradiated mice. Gene expression profiling and DNA methylation analysis identified two novel factors related to the observed effects, Tppp, associated with microtubule stabilization, and GAD2/65, associated with neuronal signaling. Our results show that lithium treatment reverses irradiation-induced loss of hippocampal neurogenesis and cognitive impairment even when introduced long after the injury. We propose that lithium treatment should be intermittent in order to first make neural progenitors proliferate and then, upon discontinuation, allow them to differentiate. Our findings suggest that pharmacological treatment of cognitive so-called late effects in childhood cancer survivors is possible.

Unavailability of old antibiotics threatens effective treatment for common bacterial infections

Summary Background The spread of antibiotic-resistant bacteria poses a substantial threat to morbidity and mortality worldwide. Due to its large public health and societal implications, multidrug-resistant tuberculosis has been long regarded by WHO as a global priority for investment in new drugs. In 2016, WHO was requested by member states to create a priority list of other antibiotic-resistant bacteria to support research and development of effective drugs. Methods We used a multicriteria decision analysis method to prioritise antibiotic-resistant bacteria; this method involved the identification of relevant criteria to assess priority against which each antibiotic-resistant bacterium was rated. The final priority ranking of the antibiotic-resistant bacteria was established after a preference-based survey was used to obtain expert weighting of criteria. Findings We selected 20 bacterial species with 25 patterns of acquired resistance and ten criteria to assess priority: mortality, health-care burden, community burden, prevalence of resistance, 10-year trend of resistance, transmissibility, preventability in the community setting, preventability in the health-care setting, treatability, and pipeline. We stratified the priority list into three tiers (critical, high, and medium priority), using the 33rd percentile of the bacterium's total scores as the cutoff. Critical-priority bacteria included carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa , and carbapenem-resistant and third-generation cephalosporin-resistant Enterobacteriaceae. The highest ranked Gram-positive bacteria (high priority) were vancomycin-resistant Enterococcus faecium and meticillin-resistant Staphylococcus aureus . Of the bacteria typically responsible for community-acquired infections, clarithromycin-resistant Helicobacter pylori , and fluoroquinolone-resistant Campylobacter spp, Neisseria gonorrhoeae , and Salmonella typhi were included in the high-priority tier. Interpretation Future development strategies should focus on antibiotics that are active against multidrug-resistant tuberculosis and Gram-negative bacteria. The global strategy should include antibiotic-resistant bacteria responsible for community-acquired infections such as Salmonella spp, Campylobacter spp, N gonorrhoeae , and H pylori . Funding World Health Organization.

Few biologists have studied the evolutionary processes at work in indoor environments. Yet indoor environments comprise approximately 0.5% of ice-free land area--an area as large as the subtropical coniferous forest biome. Here we review the emerging subfield of 'indoor biome' studies. After defining the indoor biome and tracing its deep history, we discuss some of its evolutionary dimensions. We restrict our examples to the species found in human houses--a subset of the environments constituting the indoor biome--and offer preliminary hypotheses to advance the study of indoor evolution. Studies of the indoor biome are situated at the intersection of evolutionary ecology, anthropology, architecture, and human ecology and are well suited for citizen science projects, public outreach, and large-scale international collaborations.

Sclerosing epithelioid fibrosarcoma (SEF) is a rare, malignant fibroblastic neoplasm, morphologically composed of cords, nests or sheets of monotonous epithelioid cells within a collagenous matrix. It has been recently characterized by recurrent pathogenic EWS-CREB3L1/2 or FUS-CREB3L2 fusions and common MUC4 protein expression by immunohistochemistry. Typically SEF occur in middle-aged adults and rarely have been reported within the abdominal cavity. Here we report an 18-year-old man with intraabdominal tumor and multiple disseminated liver metastases, presenting pure SEF histologic and immunophenotypic features. Fluorescence in situ hybridization analysis showed unbalanced rearrangement of Ewing sarcoma breakpoint region 1 (EWSR1) gene. Genomic profiling by array CGH, followed by RT-PCR and sequencing analysis, revealed a previously not reported EWSR1 translocation partner, cAMP-responsive element-binding protein 3-like 3 (CREB3L3). The novel EWSR1-CREB3L3 fusion further extends the range of fusion types involving EWSR1 that are characteristic for SEF.