A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas

Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential

Sepsis among Neonates in a Ghanaian Tertiary Military Hospital: Culture Results and Turnaround Times.

In this study, we described the bacterial profile, antibiotic resistance pattern, and laboratory result turnaround time (TAT) in neonates with suspected sepsis from a tertiary-level, military hospital in Accra, Ghana (2017-2020). This was a cross-sectional study using secondary data from electronic medical records. Of 471 neonates clinically diagnosed with suspected sepsis in whom blood samples were collected, the median TAT from culture request to report was three days for neonates who were culture-positive and five days for neonates who were culture-negative. There were 241 (51%) neonates discharged before the receipt of culture reports, and of them, 37 (15%) were culture-positive. Of 471 neonates, twenty-nine percent (n = 139) were bacteriologically confirmed, of whom 61% (n = 85) had late-onset sepsis. Gram-positive bacterial infection (89%, n = 124) was the most common cause of culture-positive neonatal sepsis. The most frequent Gram-positive pathogen was coagulase-negative Staphylococcus (55%, n = 68) followed by Staphylococcus aureus (36%, n = 45), of which one in two were multidrug resistant. The reasons for large numbers being discharged before the receipt of culture reports need to be further explored. There is a need for improved infection prevention and control, along with ongoing local antimicrobial resistance surveillance and antibiotic stewardship to guide future empirical treatment

Indicators and Benchmarks for Wind Erosion Monitoring, Assessment and Management

Wind erosion and blowing dust threaten food security, human health and ecosystem services across global drylands. Monitoring wind erosion is needed to inform management, with explicit monitoring objectives being critical for interpreting and translating monitoring information into management actions. Monitoring objectives should establish quantitative guidelines for determining the relationship of wind erosion indicators to management benchmarks that reflect tolerable erosion and dust production levels considering impacts to, for example, ecosystem processes, species, agricultural production systems and human well-being. Here we: 1) critically review indicators of wind erosion and blowing dust that are currently available to practitioners; and 2) describe approaches for establishing benchmarks to support wind erosion assessments and management. We find that while numerous indicators are available for monitoring wind erosion, only a subset have been used routinely and most monitoring efforts have focused on air quality impacts of dust. Indicators need to be related to the causal soil and vegetation controls in eroding areas to directly inform management. There is great potential to use regional standardized soil and vegetation monitoring datasets, remote sensing and models to provide new information on wind erosion across landscapes. We identify best practices for establishing benchmarks for these indicators based on experimental studies, mechanistic and empirical models, and distributions of indicator values obtained from monitoring data at historic or existing reference sites. The approaches to establishing benchmarks described here have enduring utility as monitoring technologies change and enable managers to evaluate co-benefits and potential trade-offs among ecosystem services as affected by wind erosion management

An Update on the Surveillance of Livestock Diseases and Antimicrobial Use in Sierra Leone in 2021-An Operational Research Study.

In Sierra Leone, in 2020, a study by the Livestock and Veterinary Services Division (Ministry of Agriculture and Forestry) on the surveillance system of animal diseases and antimicrobial use found poor reporting. Of the expected weekly districts reports, <1% were received and only three of the 15 districts had submitted reports occasionally between 2016 and 2019. Following this, staff-capacity-building on reporting was undertaken. In 2021, we reassessed the improvement in reporting and used the reports to describe livestock diseases and antimicrobials utilized in their treatment. Between March and October 2021, 88% of expected weekly reports from all 15 districts were received. There were minor deficiencies in completeness and consistency in the terminology used for reporting animal disease and antimicrobials. Available reports showed that 25% of the livestock had an infectious disease, and a quarter of the sick animals had received an antimicrobial drug. Most animals received antimicrobials belonging to World Organization for Animal Health's "veterinary critically important" category (77%) and World Health Organization's "critically" (17%) and "highly important" (60%) categories for human health. These indicate a significant improvement in the animal health surveillance system and highlight the need for enhanced antimicrobial stewardship to prevent misuse of antimicrobials that are significant in animal and human health

Indicators and benchmarks for wind erosion monitoring, assessment and management

Wind erosion and blowing dust threaten food security, human health and ecosystem services across global drylands. Monitoring wind erosion is needed to inform management, with explicit monitoring objectives being critical for interpreting and translating monitoring information into management actions. Monitoring objectives should establish quantitative guidelines for determining the relationship of wind erosion indicators to management benchmarks that reflect tolerable erosion and dust production levels considering impacts to, for example, ecosystem processes, species, agricultural production systems and human well-being. Here we: 1) critically review indicators of wind erosion and blowing dust that are currently available to practitioners; and 2) describe approaches for establishing benchmarks to support wind erosion assessments and management. We find that while numerous indicators are available for monitoring wind erosion, only a subset have been used routinely and most monitoring efforts have focused on air quality impacts of dust. Indicators need to be related to the causal soil and vegetation controls in eroding areas to directly inform management. There is great potential to use regional standardized soil and vegetation monitoring datasets, remote sensing and models to provide new information on wind erosion across landscapes. We identify best practices for establishing benchmarks for these indicators based on experimental studies, mechanistic and empirical models, and distributions of indicator values obtained from monitoring data at historic or existing reference sites. The approaches to establishing benchmarks described here have enduring utility as monitoring technologies change and enable managers to evaluate co-benefits and potential trade-offs among ecosystem services as affected by wind erosion management

Friedrich Hayek and his visits to Chile

F. A. Hayek took two trips to Chile, the first in 1977, the second in 1981. The visits were controversial. On the first trip he met with General Augusto Pinochet, who had led a coup that overthrew Salvador Allende in 1973. During his 1981 visit, Hayek gave interviews that were published in the Chilean newspaper El Mercurio and in which he discussed authoritarian regimes and the problem of unlimited democracy. After each trip, he complained that the western press had painted an unfair picture of the economic situation under the Pinochet regime. Drawing on archival material, interviews, and past research, we provide a full account of this controversial episode in Hayek’s life

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

The United States COVID-19 Forecast Hub dataset

Academic researchers, government agencies, industry groups, and individuals have produced forecasts at an unprecedented scale during the COVID-19 pandemic. To leverage these forecasts, the United States Centers for Disease Control and Prevention (CDC) partnered with an academic research lab at the University of Massachusetts Amherst to create the US COVID-19 Forecast Hub. Launched in April 2020, the Forecast Hub is a dataset with point and probabilistic forecasts of incident cases, incident hospitalizations, incident deaths, and cumulative deaths due to COVID-19 at county, state, and national, levels in the United States. Included forecasts represent a variety of modeling approaches, data sources, and assumptions regarding the spread of COVID-19. The goal of this dataset is to establish a standardized and comparable set of short-term forecasts from modeling teams. These data can be used to develop ensemble models, communicate forecasts to the public, create visualizations, compare models, and inform policies regarding COVID-19 mitigation. These open-source data are available via download from GitHub, through an online API, and through R packages

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701