192 research outputs found

    Emerging themes in population consequences of disturbance models

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    Funding: K.A.K., R.S.B. and D.P.C. were supported by the E&P Sound and Marine Life Joint Industry Programme (JIP) of the International Association of Oil and Gas Producers (IOGP) (grant no. 00-07-23). K.A.K. was also supported by the National Defense Science and Engineering Graduate (NDSEG) Fellowship. E.P. was supported by the Office of Naval Research (ONR) (grant no. N00014-19-1-2464). D.P.C. was also supported by ONR (grant no. N00014-18-1-2822).Assessing the non-lethal effects of disturbance from human activities is necessary for wildlife conservation and management. However, linking short-term responses to long-term impacts on individuals and populations is a significant hurdle for evaluating the risks of a proposed activity. The Population Consequences of Disturbance (PCoD) framework conceptually describes how disturbance can lead to changes in population dynamics, and its real-world application has led to a suite of quantitative models that can inform risk assessments. Here, we review PCoD models that forecast the possible consequences of a range of disturbance scenarios for marine mammals. In so doing, we identify common themes and highlight general principles to consider when assessing risk. We find that, when considered holistically, these models provide valuable insights into which contextual factors influence a population's degree of exposure and sensitivity to disturbance. We also discuss model assumptions and limitations, identify data gaps and suggest future research directions to enable PCoD models to better inform risk assessments and conservation and management decisions. The general principles explored can help wildlife managers and practitioners identify and prioritize the populations most vulnerable to disturbance and guide industry in planning activities that avoid or mitigate population-level effects.Publisher PDFPeer reviewe

    Temporal trends of time to antiretroviral treatment initiation, interruption and modification: Examination of patients diagnosed with advanced HIV in Australia

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    INTRODUCTION: HIV prevention strategies are moving towards reducing plasma HIV RNA viral load in all HIV-positive persons, including those undiagnosed, treatment naïve, on or off antiretroviral therapy. A proxy population for those undiagnosed are patients that present late to care with advanced HIV. The objectives of this analysis are to examine factors associated with patients presenting with advanced HIV, and establish rates of treatment interruption and modification after initiating ART. METHODS: We deterministically linked records from the Australian HIV Observational Database to the Australian National HIV Registry to obtain information related to HIV diagnosis. Logistic regression was used to identify factors associated with advanced HIV diagnosis. We used survival methods to evaluate rates of ART initiation by diagnosis CD4 count strata and by calendar year of HIV diagnosis. Cox models were used to determine hazard of first ART treatment interruption (duration >30 days) and time to first major ART modification. RESULTS: Factors associated (p<0.05) with increased odds of advanced HIV diagnosis were sex, older age, heterosexual mode of HIV exposure, born overseas and rural-regional care setting. Earlier initiation of ART occurred at higher rates in later periods (2007-2012) in all diagnosis CD4 count groups. We found an 83% (69, 91%) reduction in the hazard of first treatment interruption comparing 2007-2012 versus 1996-2001 (p<0.001), and no difference in ART modification for patients diagnosed with advanced HIV. CONCLUSIONS: Recent HIV diagnoses are initiating therapy earlier in all diagnosis CD4 cell count groups, potentially lowering community viral load compared to earlier time periods. We found a marked reduction in the hazard of first treatment interruption, and found no difference in rates of major modification to ART by HIV presentation status in recent periods

    Cis and trans regulatory mechanisms control AP2-mediated B cell receptor endocytosis via select tyrosine-based motifs.

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    Following antigen recognition, B cell receptor (BCR)-mediated endocytosis is the first step of antigen processing and presentation to CD4+ T cells, a crucial component of the initiation and control of the humoral immune response. Despite this, the molecular mechanism of BCR internalization is poorly understood. Recently, studies of activated B cell-like diffuse large B cell lymphoma (ABC DLBCL) have shown that mutations within the BCR subunit CD79b leads to increased BCR surface expression, suggesting that CD79b may control BCR internalization. Adaptor protein 2 (AP2) is the major mediator of receptor endocytosis via clathrin-coated pits. The BCR contains five putative AP2-binding YxxØ motifs, including four that are present within two immunoreceptor tyrosine-based activation motifs (ITAMs). Using a combination of in vitro and in situ approaches, we establish that the sole mediator of AP2-dependent BCR internalization is the membrane proximal ITAM YxxØ motif in CD79b, which is a major target of mutation in ABC DLBCL. In addition, we establish that BCR internalization can be regulated at a minimum of two different levels: regulation of YxxØ AP2 binding in cis by downstream ITAM-embedded DCSM and QTAT regulatory elements and regulation in trans by the partner cytoplasmic domain of the CD79 heterodimer. Beyond establishing the basic rules governing BCR internalization, these results illustrate an underappreciated role for ITAM residues in controlling clathrin-dependent endocytosis and highlight the complex mechanisms that control the activity of AP2 binding motifs in this receptor system

    Early Results from GLASS-JWST. VIII. An Extremely Magnified Blue Supergiant Star at Redshift 2.65 in the A2744 Cluster Field

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    We report the discovery of an extremely magnified star at redshift z = 2.65 in the James Webb Space Telescope (JWST) NIRISS pre-imaging of the A2744 galaxy-cluster field. The star's background host galaxy lies on a fold caustic of the foreground lens, and the cluster creates a pair of images of the region close to the lensed star. We identified the bright transient in one of the merging images at a distance of similar to 0.'' 15 from the critical curve by subtracting the JWST F115W and F150W imaging from coadditions of archival Hubble Space Telescope (HST) F105W and F125W images and F140W and F160W images, respectively. Since the time delay between the two images should be only hours, the transient must be the microlensing event of an individual star, as opposed to a luminous stellar explosion that would persist for days to months. Analysis of individual exposures suggests that the star's magnification is not changing rapidly during the observations. From photometry of the point source through the F115W, F150W, and F200W filters, we identify a strong Balmer break, and modeling allows us to constrain the star's temperature to be approximately 7000-12,000 K.This work is based on observations made with the NASA/ESA/CSA James Webb Space Telescope. The data were obtained from the Mikulski Archive for Space Telescopes at the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., under NASA contract NAS 5-03127 for JWST. These observations are associated with program JWST-ERS-1324. The specific observations analyzed can be accessed via 10.17909/y6dh-6g16. We acknowledge financial support from NASA through grant JWST-ERS-1324. Archival images from the Hubble Space Telescope were also used. We would like to thank Dr. Pietro Bergamini, Prof. Piero Rosati, Prof. Claudio Grillo, Dr. Ana Acebron, and Dr. Eros Vanzella for their helpful comments on our paper and for sharing the predictions of their lens model.W.C. acknowledges support from NASA HST grant AR-15791. P.L.K. is supported by NSF grant AST-1908823 and NASA/Keck JPL RSA 1644110. R.A.W. acknowledges support from NASA JWST Interdisciplinary Scientist grants NAG5-12460, NNX14AN10G, and 80NSSC18K0200 from GSFC. J.M.D. acknowledges the support of project PGC2018-101814-B-100 (MCIU/AEI/MINECO/FEDER, UE) Ministerio de Ciencia, Investigacion y Universidades. This project was funded by the Agencia Estatal de Investigacion, Unidad de Excelencia Maria de Maeztu, ref. MDM-2017-0765. A.K. is supported by scientist grants NAG5-12460, NNX14AN10G, and 80NSSC18K0200 from GSFC. A.Z. and A.K.M. acknowledge support by Grant No. 2020750 from the United States-Israel Binational Science Foundation (BSF) and grant No. 2109066 from the United States National Science Foundation (NSF), and by the Ministry of Science & Technology, Israel. M.B. acknowledges support from the Slovenian national research agency ARRS through grant N1-0238

    Key questions in marine mammal bioenergetics

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    This work was funded by the Marine Mammal Commission (MMC19-173). The Office of Naval Research funded the bioenergetic workshop (N000142012392) that provided support for this work.Bioenergetic approaches are increasingly used to understand how marine mammal populations could be affected by a changing and disturbed aquatic environment. There remain considerable gaps in our knowledge of marine mammal bioenergetics, which hinder the application of bioenergetic studies to inform policy decisions. We conducted a priority-setting exercise to identify high-priority unanswered questions in marine mammal bioenergetics, with an emphasis on questions relevant to conservation and management. Electronic communication and a virtual workshop were used to solicit and collate potential research questions from the marine mammal bioenergetic community. From a final list of 39 questions, 11 were identified as ‘key’ questions because they received votes from at least 50% of survey participants. Key questions included those related to energy intake (prey landscapes, exposure to human activities) and expenditure (field metabolic rate, exposure to human activities, lactation, time-activity budgets), energy allocation priorities, metrics of body condition and relationships with survival and reproductive success and extrapolation of data from one species to another. Existing tools to address key questions include labelled water, animal-borne sensors, mark-resight data from long-term research programs, environmental DNA and unmanned vehicles. Further validation of existing approaches and development of new methodologies are needed to comprehensively address some key questions, particularly for cetaceans. The identification of these key questions can provide a guiding framework to set research priorities, which ultimately may yield more accurate information to inform policies and better conserve marine mammal populations.Publisher PDFPeer reviewe

    Chronic illness and multimorbidity among problem drug users: a comparative cross sectional pilot study in primary care

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    <p>Abstract</p> <p>Background</p> <p>Although multimorbidity has important implications for patient care in general practice, limited research has examined chronic illness and health service utilisation among problem drug users. This study aimed to determine chronic illness prevalence and health service utilisation among problem drug users attending primary care for methadone treatment, to compare these rates with matched 'controls' and to develop and pilot test a valid study instrument.</p> <p>Methods</p> <p>A cross-sectional study of patients attending three large urban general practices in Dublin, Ireland for methadone treatment was conducted, and this sample was compared with a control group matched by practice, age, gender and General Medical Services (GMS) status.</p> <p>Results</p> <p>Data were collected on 114 patients. Fifty-seven patients were on methadone treatment, of whom 52(91%) had at least one chronic illness (other then substance use) and 39(68%) were prescribed at least one regular medication. Frequent utilisation of primary care services and secondary care services in the previous six months was observed among patients on methadone treatment and controls, although the former had significantly higher chronic illness prevalence and primary care contact rates. The study instrument facilitated data collection that was feasible and with minimal inter-observer variation.</p> <p>Conclusion</p> <p>Multimorbidity is common among problem drug users attending general practice for methadone treatment. Primary care may therefore have an important role in primary and secondary prevention of chronic illnesses among this population. This study offers a feasible study instrument for further work on this issue. (238 words)</p

    Prevalence of problem alcohol use among patients attending primary care for methadone treatment

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    <p>Abstract</p> <p>Background</p> <p>Problem alcohol use is associated with adverse health outcomes among current or former heroin users and primary care is providing methadone treatment for increasing numbers of this population. This study aimed todetermine the prevalence of problem alcohol use among current or former heroin users attending primary care for methadone treatment and to describe the socio-demographic characteristics and health service utilisation characteristics associated with problem alcohol uses.</p> <p>Methods</p> <p>We conducted a cross sectional survey of patients sampled from a national database of patients attending general practice for methadone treatment. Participants were recruited by their general practitioner and data was collected using an interviewer-administered questionnaire, which included the Alcohol Use Disorders Identification Test ('AUDIT'), with a score of >7 considered abnormal (ie 'AUDIT positive cases') and socio-demographic, medical and substance use characteristics.</p> <p>Results</p> <p>We interviewed 196 patients (71% of those invited, 31% of those sampled, 11% of the national database). The median age was 32 years, 55% were hepatitis C positive, 79% had used illicit drugs in the previous month and 68% were male. Sixty-eight 'AUDIT positive' cases were identified (prevalence of 35%, 95% CI = 28–41%) and these were more likely to have attended a local Emergency Department in the previous year (p < 0.05) and less likely to have attended a hospital clinic in the previous year (p < 0.05). Twenty-seven (14%) scored 20 or higher indicating possible alcohol dependence.</p> <p>Conclusion</p> <p>Problem alcohol use has a high prevalence among current or former heroin users attending primary care for methadone treatment and interventions that address this issue should be explored as a priority. Interventions that address problem alcohol use in this population should be considered as a priority, although the complex medical and psychological needs of this population may make this challenging.</p

    Combined use of bacteriophage K and a novel bacteriophage to reduce Staphylococcus aureus biofilm formation

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    Biofilms are major causes of impairment of wound healing and patient morbidity. One of the most common and aggressive wound pathogens is Staphylococcus aureus, displaying a large repertoire of virulence factors and commonly reduced susceptibility to antibiotics, such as the spread of methicillin-resistant S. aureus (MRSA). Bacteriophages are obligate parasites of bacteria. They multiply intracellularly and lyse their bacterial host, releasing their progeny. We isolated a novel phage, DRA88, which has a broad host range among S. aureus bacteria. Morphologically, the phage belongs to the Myoviridae family and comprises a large double-stranded DNA (dsDNA) genome of 141,907 bp. DRA88 was mixed with phage K to produce a high-titer mixture that showed strong lytic activity against a wide range of S. aureus isolates, including representatives of the major international MRSA clones and coagulase-negative Staphylococcus. Its efficacy was assessed both in planktonic cultures and when treating established biofilms produced by three different biofilm-producing S. aureus isolates. A significant reduction of biofilm biomass over 48 h of treatment was recorded in all cases. The phage mixture may form the basis of an effective treatment for infections caused by S. aureus biofilms

    Cell-based screen for altered nuclear phenotypes reveals senescence progression in polyploid cells after Aurora kinase B inhibition.

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    Cellular senescence is a widespread stress response and is widely considered to be an alternative cancer therapeutic goal. Unlike apoptosis, senescence is composed of a diverse set of subphenotypes, depending on which of its associated effector programs are engaged. Here we establish a simple and sensitive cell-based prosenescence screen with detailed validation assays. We characterize the screen using a focused tool compound kinase inhibitor library. We identify a series of compounds that induce different types of senescence, including a unique phenotype associated with irregularly shaped nuclei and the progressive accumulation of G1 tetraploidy in human diploid fibroblasts. Downstream analyses show that all of the compounds that induce tetraploid senescence inhibit Aurora kinase B (AURKB). AURKB is the catalytic component of the chromosome passenger complex, which is involved in correct chromosome alignment and segregation, the spindle assembly checkpoint, and cytokinesis. Although aberrant mitosis and senescence have been linked, a specific characterization of AURKB in the context of senescence is still required. This proof-of-principle study suggests that our protocol is capable of amplifying tetraploid senescence, which can be observed in only a small population of oncogenic RAS-induced senescence, and provides additional justification for AURKB as a cancer therapeutic target.This work was supported by the University of Cambridge, Cancer Research UK, Hutchison Whampoa; Cancer Research UK grants A6691 and A9892 (M.N., N.K., C.J.T., D.C.B., C.J.C., L.S.G, and M.S.); a fellowship from the Uehara Memorial Foundation (M.S.).This is the author accepted manuscript. The final version is available from the American Society for Cell Biology via http://dx.doi.org/10.1091/mbc.E15-01-000

    Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

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    BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700
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