Oral Apolipoprotein A-I Mimetic D-4F Lowers HDL-Inflammatory Index in High-Risk Patients: A First-in-Human Multiple-Dose, Randomized Controlled Trial.

A single dose of the apolipoprotein (apo)A-I mimetic peptide D-4F rendered high-density lipoprotein (HDL) less inflammatory, motivating the first multiple-dose study. We aimed to assess safety/tolerability, pharmacokinetics, and pharmacodynamics of daily, orally administered D-4F. High-risk coronary heart disease (CHD) subjects added double-blinded placebo or D-4F to statin for 13 days, randomly assigned 1:3 to ascending cohorts of 100, 300, then 500 mg (n = 62; 46 men/16 women). D-4F was safe and well-tolerated. Mean ± SD plasma D-4F area under the curve (AUC, 0-8h) was 6.9 ± 5.7 ng/mL*h (100 mg), 22.7 ± 19.6 ng/mL*h (300 mg), and 104.0 ± 60.9 ng/mL*h (500 mg) among men, higher among women. Whereas placebo dropped HDL inflammatory index (HII) 28% 8 h postdose (range, 1.25-0.86), 300-500 mg D-4F effectively halved HII: 1.35-0.57 and 1.22-0.63, respectively (P \u3c 0.03 vs. placebo). Oral D-4F peptide dose predicted HII suppression, whereas plasma D-4F exposure was dissociated, suggesting plasma penetration is unnecessary. In conclusion, oral D-4F dosing rendered HDL less inflammatory, affirming oral D-4F as a potential therapy to improve HDL function

Experimental Inoculation of Coyotes with \u3ci\u3eMycobacterium bovis\u3c/i\u3e Susceptibility and Shedding

Several wildlife species have tested positive for bovine tuberculosis in Michigan and may potentially transmit the disease to other animals. Coyotes have the highest known prevalence in the endemic area and thus, our objective was to investigate the shedding of Mycobacterium bovis by coyotes. Four coyotes were orally inoculated with 1 ml of 1 x 105 CFU/ml of M. bovis. Oral and nasal swabs, and feces were collected regularly and tested by culture. Fecal samples were also tested by exposing guinea pigs to the coyotes\u27 feces. All animals were necropsied to determine if infection occurred. All swabs, feces and tissues were negative on culture. The dosage of M. bovis given to these coyotes was considered biologically relevant, but was insufficient for causing infection. Due to the lack of infection, we still do not know the risk coyotes pose for shedding M. bovis

Mantle to surface degassing of alkalic magmas at Erebus volcano, Antarctica

International audienceContinental intraplate volcanoes, such as Erebus volcano, Antarctica, are associated with extensional tectonics, mantle upwelling and high heat flow. Typically, erupted magmas are alkaline and rich in volatiles (especially CO2), inherited from low degrees of partial melting of mantle sources. We examine the degassing of the magmatic system at Erebus volcano using melt inclusion data and high temporal resolution open-path Fourier transform infrared (FTIR) spectroscopic measurements of gas emissions from the active lava lake. Remarkably different gas signatures are associated with passive and explosive gas emissions, representative of volatile contents and redox conditions that reveal contrasting shallow and deep degassing sources. We show that this unexpected degassing signature provides a unique probe for magma differentiation and transfer of CO2-rich oxidised fluids from the mantle to the surface, and evaluate how these processes operate in time and space. Extensive crystallisation driven by CO2 fluxing is responsible for isobaric fractionation of parental basanite magmas close to their source depth. Magma deeper than 4 kbar equilibrates under vapour-buffered conditions. At shallower depths, CO2-rich fluids accumulate and are then released either via convection-driven, open-system gas loss or as closed-system slugs that ascend and result in Strombolian eruptions in the lava lake. The open-system gases have a reduced state (below the QFM buffer) whereas the closed-system gases preserve their deep oxidised signatures (close to the NNO buffer)

Revising ethical guidance for the evaluation of programmes and interventions not initiated by researchers

Public health and service delivery programmes, interventions and policies (collectively, ‘programmes’) are typically developed and implemented for the primary purpose of effecting change rather than generating knowledge. Nonetheless, evaluations of these programmes may produce valuable learning that helps determine effectiveness and costs as well as informing design and implementation of future programmes. Such studies might be termed ‘opportunistic evaluations’, since they are responsive to emergent opportunities rather than being studies of interventions that are initiated or designed by researchers. However, current ethical guidance and registration procedures make little allowance for scenarios where researchers have played no role in the development or implementation of a programme, but nevertheless plan to conduct a prospective evaluation. We explore the limitations of the guidance and procedures with respect to opportunistic evaluations, providing a number of examples. We propose that one key missing distinction in current guidance is moral responsibility: researchers can only be held accountable for those aspects of a study over which they have control. We argue that requiring researchers to justify an intervention, programme or policy that would occur regardless of their involvement prevents or hinders research in the public interest without providing any further protections to research participants. We recommend that trial consent and ethics procedures allow for a clear separation of responsibilities for the intervention and the evaluation

Understanding Middle Neolithic food and farming in and around the Stonehenge World Heritage Site: an integrated approach

Little synthesis of evidence for Middle Neolithic food and farming in Wiltshire, particularly in and around the Stonehenge World Heritage Site (WHS) has been possible, until now, due to a paucity of assemblages. The excavation of a cluster of five Middle Neolithic pits and an inhumation burial at West Amesbury Farm (WAF) has prompted a review of our understanding of pit sites of this period from the county. Bioarchaeological assemblages are used to investigate evidence for the consumption of animal and plant-based foods, and for agricultural and pastoral farming. For the first time Middle Neolithic zooarchaeological evidence, including strontium isotope data, is considered alongside archaeobotanical data, and radiocarbon dating. The absence of cultivated plants from WAF and contemporary sites in the county is consistent with the hypothesis that the reduction in cereal cultivation and greater reliance of wild plants witnessed in the later part of the Neolithic in southern England began in the Middle Neolithic. The zooarchaeological evidence from the same sites demonstrates that the shift away from cereal cultivation may be concurrent with, rather than earlier than, an increase in the relative proportion of deposited pig bones relative to cattle. Both cattle and pigs deposited in pits at WAF have strontium and sulphur isotope values consistent with the local biosphere, and therefore were potentially raised in the area. Zooarchaeological data from WAF compliments that from human dental calculus and lipid residues in associated Peterborough Ware pottery that local cattle husbandry included exploitation of dairy. It also highlights the presence of consistent food preparation methods between pits as seen through butchery practice. The faunal and archaeobotanical remains from contemporary pit deposits suggest that similar farming and subsistence strategies can be proposed across the county, though with some inter-site variation in deposition. Together these excavated pit sites are likely to represent only a sample of those present in the area. Application of a similar integrated approach to material from other Middle Neolithic pits holds potential for better understanding of food and farming in this previously neglected period

A retrospective analysis of clinical use of alirocumab in lipoprotein apheresis patients

BACKGROUND: The previously published ODYSSEY ESCAPE trial demonstrated a significant reduction in the use of lipoprotein apheresis for heterozygous familial hypercholesterolemia (HeFH) patients when placed on alirocumab 150 mg every 2 weeks. In patients with HeFH who have consistently elevated levels of low-density lipoprotein cholesterol (LDL-C) despite maximally tolerated statin therapy, current lipid guidelines recommend apheresis. Although apheresis reduces LDL-C levels by 50%-75%, it must be repeated, as frequently as every 1-2 weeks. OBJECTIVE: To assess clinical experience with apheresis and alirocumab for patients in a real-world practice setting. METHODS: This retrospective review included patients from 5 apheresis centers who were treated with apheresis and had started alirocumab therapy. In addition to LDL-C levels, total cholesterol, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, and particle numbers were evaluated if data were available. RESULTS: Eleven of the 25 (44%) patients discontinued apheresis completely after initiation of alirocumab therapy, having achieved LDL-C \u3c70 mg/dL or \u3e50% reduction from baseline levels. Among the 14 patients who remained on apheresis, seven decreased the frequency of apheresis sessions. No significant safety problems were reported. CONCLUSION: Alirocumab lowered LDL-C levels by an average of 55.5% in patients receiving apheresis for elevated LDL-C. Seventy-two percent of patients on alirocumab therapy discontinued or reduced the frequency of apheresis treatment. However, some patients continued to require apheresis due to elevated lipoprotein(a), extremely elevated LDL-C, or if alirocumab therapy was discontinued due to less than anticipated LDL-C reduction

Evaluating the impact of a community health worker program on non-communicable disease, malnutrition, tuberculosis, family planning and antenatal care in Neno, Malawi : protocol for a stepped-wedge, cluster randomized controlled trial

Introduction: This protocol concerns the implementation and evaluation of an intervention designed to realign the existing cadre of Community Health Workers (CHWs) in Neno District, Malawi to better support the care needs of the clients they serve. The proposed intervention is a ‘Household Model’ where CHWs will be reassigned to households, rather than to specific patients with HIV and/or TB. Methods and Analysis: Using a stepped-wedge, cluster-randomized design, this study investigates whether high HIV retention rates can be replicated for non-communicable diseases (NCDs), and the Model’s impact on TB and pediatric malnutrition case-finding, as well as the uptake of family planning and antenatal care. Eleven sites (health centres and hospitals) were arranged into six clusters (average cluster population 21,800). Primary outcomes include retention in care for HIV and chronic NCDs, TB case finding, pediatric malnutrition case finding, and utilization of early and complete antenatal. Clinical outcomes are based on routinely collected data the Ministry of Health’s District Health Information System 2 and an OpenMRS Electronic Medical Record supported by Partners In Health. Additionally, semi-structured qualitative interviews with various stakeholders will assess community perceptions and context of the Household Model. Ethics and dissemination: Ethics approval has been obtained from the Malawian National Health Science Research Committee (#16/11/1694) in Lilongwe, Malawi; Partners Healthcare Human Research Committee (#2017P000548/PHS) in Somerville, Massachusetts; and by the Biomedical and Scientific Research Ethics Sub-Committee (REGO-2017-2060) at the University of Warwick in Coventry, United Kingdom. Dissemination will include manuscripts for peer-reviewed publication as well as a full report detailing the findings of the intervention for the Malawian Ministry of Health. Registration: Registered on ClinicalTrials.gov in April 2017. Identifier: NCT0310672

Grooming coercion and the post-conflict trading of social services in wild Barbary macaques

In animal and human societies, social services such as protection from predators are often exchanged between group members. The tactics that individuals display to obtain a service depend on its value and on differences between individuals in their capacity to aggressively obtain it. Here we analysed the exchange of valuable social services (i.e. grooming and relationship repair) in the aftermath of a conflict, in wild Barbary macaques (Macaca sylvanus). The relationship repair function of post-conflict affiliation (i.e. reconciliation) was apparent in the victim but not in the aggressor. Conversely, we found evidence for grooming coercion by the aggressor; when the victim failed to give grooming soon after a conflict they received renewed aggression from the aggressor. We argue that post-conflict affiliation between former opponents can be better described as a trading of social services rather than coercion alone, as both animals obtain some benefits (i.e. grooming for the aggressor and relationship repair for the victim). Our study is the first to test the importance of social coercion in the aftermath of a conflict. Differences in competitive abilities can affect the exchange of services and the occurrence of social coercion in animal societies. This may also help explain the variance between populations and species in their social behaviour and conflict management strategies

Development of Resistance to Type II JAK2 Inhibitors in MPN Depends on AXL Kinase and Is Targetable

PURPOSE: Myeloproliferative neoplasms (MPN) dysregulate JAK2 signaling. Because clinical JAK2 inhibitors have limited disease-modifying effects, type II JAK2 inhibitors such as CHZ868 stabilizing inactive JAK2 and reducing MPN clones, gain interest. We studied whether MPN cells escape from type ll inhibition. EXPERIMENTAL DESIGN: MPN cells were continuously exposed to CHZ868. We used phosphoproteomic analyses and ATAC/RNA sequencing to characterize acquired resistance to type II JAK2 inhibition, and targeted candidate mediators in MPN cells and mice. RESULTS: MPN cells showed increased IC50 and reduced apoptosis upon CHZ868 reflecting acquired resistance to JAK2 inhibition. Among \u3e2,500 differential phospho-sites, MAPK pathway activation was most prominent, while JAK2-STAT3/5 remained suppressed. Altered histone occupancy promoting AP-1/GATA binding motif exposure associated with upregulated AXL kinase and enriched RAS target gene profiles. AXL knockdown resensitized MPN cells and combined JAK2/AXL inhibition using bemcentinib or gilteritinib reduced IC50 to levels of sensitive cells. While resistant cells induced tumor growth in NOD/SCID gamma mice despite JAK2 inhibition, JAK2/AXL inhibition largely prevented tumor progression. Because inhibitors of MAPK pathway kinases such as MEK are clinically used in other malignancies, we evaluated JAK2/MAPK inhibition with trametinib to interfere with AXL/MAPK-induced resistance. Tumor growth was halted similarly to JAK2/AXL inhibition and in a systemic cell line-derived mouse model, marrow infiltration was decreased supporting dependency on AXL/MAPK. CONCLUSIONS: We report on a novel mechanism of AXL/MAPK-driven escape from type II JAK2 inhibition, which is targetable at different nodes. This highlights AXL as mediator of acquired resistance warranting inhibition to enhance sustainability of JAK2 inhibition in MPN

Potential for diagnosis of infectious disease from the 100,000 Genomes Project Metagenomic Dataset: Recommendations for reporting results

The identification of microbiological infection is usually a diagnostic investigation, a complex process that is firstly initiated by clinical suspicion. With the emergence of high-throughput sequencing (HTS) technologies, metagenomic analysis has unveiled the power to identify microbial DNA/RNA from a diverse range of clinical samples (1). Metagenomic analysis of whole human genomes at the clinical/research interface bypasses the steps of clinical scrutiny and targeted testing and has the potential to generate unexpected findings relating to infectious and sometimes transmissible disease. There is no doubt that microbial findings that may have a significant impact on a patient’s treatment and their close contacts should be reported to those with clinical responsibility for the sample-donating patient. There are no clear recommendations on how such findings that are incidental, or outside the original investigation, should be handled. Here we aim to provide an informed protocol for the management of incidental microbial findings as part of the 100,000 Genomes Projectwhich may have broader application in this emerging field. As with any other clinical information, we aim to prioritise the reporting of data that are most likely to be of benefit to the patient and their close contacts. We also set out to minimize risks, costs and potential anxiety associated with the reporting of results that are unlikely to be of clinical significance. Our recommendations aim to support the practice of microbial metagenomics by providing a simplified pathway that can be applied to reporting the identification of potential pathogens from metagenomic datasets. Given that the ambition for UK sequenced human genomes over the next 5 years has been set to reach 5 million and the field of metagenomics is rapidly evolving, the guidance will be regularly reviewed and will likely adapt over time as experience develops