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OBJECTIVES/GOALS: Immunomodulatory drugs (IMiDs) are critical to multiple myeloma (MM) disease control. IMiDs act by inducing Cereblon-dependent degradation of IKZF1 and IKZF3, which leads to IRF4 and MYC downregulation (collectively termed the “Ikaros axis”). We therefore hypothesized that IMiD treatment fails to downregulate the Ikaros axis in IMiD resistant MM. METHODS/STUDY POPULATION: To measure IMiD-induced Ikaros axis downregulation, we designed an intracellular flow cytometry assay that measured relative protein levels of IKZF1, IKZF3, IRF4 and MYC in MM cells following ex vivo treatment with the IMiD Pomalidomide (Pom). We established this assay using Pom-sensitive parental and dose-escalated Pom-resistant MM cell lines before assessing Ikaros axis downregulation in CD38+CD138+ MM cells in patient samples (bone marrow aspirates). To assess the Ikaros axis in the context of MM intratumoral heterogeneity, we used a 35-marker mass cytometry panel to simultaneously characterize MM subpopulations in patient samples. Lastly, we determined ex vivo drug sensitivity in patient samples via flow cytometry. RESULTS/ANTICIPATED RESULTS: Our hypothesis was supported in MM cell lines, as resistant lines showed no IMiD-induced decrease in any Ikaros axis proteins. However, when assessed in patient samples, Pom treatment caused a significant decrease in IKZF1, IKZF3 and IRF4 regardless of IMiD sensitivity. Mass cytometry in patient samples revealed that individual Ikaros axis proteins were differentially expressed between subpopulations. When correlating this with ex vivo Pom sensitivity of MM subpopulations, we observed that low IKZF1 and IKZF3 corresponded to Pom resistance. Interestingly, most of these resistant populations still expressed MYC. We therefore assessed whether IMiD resistant MM was MYC dependent by treating with MYCi975. In 88% (7/8) of patient samples tested, IMiD resistant MM cells were sensitive to MYC inhibition. DISCUSSION/SIGNIFICANCE: While our findings did not support our initial hypothesis, our data suggest a mechanism where MYC expression becomes Ikaros axis independent to drive IMiD resistance, and resistant MM is still dependent on MYC. This suggests targeting MYC directly or indirectly via a mechanism to be determined may be an effective strategy to eradicate IMiD resistant MM.
We discuss present and developing techniques for studying radiocarbon in marine organic carbon (C). Bulk DOC (dissolved organic C) Δ14C measurements reveal information about the cycling time and sources of DOC in the ocean, yet they are time consuming and need to be streamlined. To further elucidate the cycling of DOC, various fractions have been separated from bulk DOC, through solid phase extraction of DOC, and ultrafiltration of high and low molecular weight DOC. Research using 14C of DOC and particulate organic C separated into organic fractions revealed that the acid insoluble fraction is similar in 14C signature to that of the lipid fraction. Plans for utilizing this methodology are described. Studies using compound specific radiocarbon analyses to study the origin of biomarkers in the marine environment are reviewed and plans for the future are outlined. Development of ramped pyrolysis oxidation methods are discussed and scientific questions addressed. A modified elemental analysis (EA) combustion reactor is described that allows high particulate organic C sample throughput by direct coupling with the MIniCArbonDAtingSystem.
The first edition of Introduction to Psychiatry is a textbook designed to reach medical students, house staff, primary care clinicians, and early-career mental health practitioners. It is the editors’ hope that this text will enable its readers to understand the neuroscientific basis of psychiatry, best practices in the psychiatric assessment and treatment of the patient, the current understanding of core psychiatric diagnoses, and the important underlying issues of population health, public policy, and workforce recruitment and training that must be tackled to bring these advances to all.
Why create a textbook of psychiatry specifically for clinicians not trained for the mental health field? To answer this question, one must understand the troubling challenges facing the mental health workforce, the changing face of mental health care delivery, the enormous comorbidity between psychiatric illnesses and other health conditions, and the impact on non-psychiatric medical illnesses when a comorbid psychiatric disorder is present.
The current global crisis in mental health has seen psychiatry assume an increasingly integral role in healthcare. This comprehensive and accessible textbook provides an evidence-based foundation in psychiatry for medical students and serves as an excellent refresher for all mental health professionals. Written by medical school faculty and experts in the field, with comprehensive coverage from neurobiology to population health, this essential textbook is an invaluable guide to the evaluation, treatment and current understanding of the major disorders in psychiatry. The book introduces the basics of clinical assessment and all major modalities of evidence based treatment, along with topics often not covered adequately in textbooks such as gender and sexuality, and global mental health. Chapters are complemented by easy to navigate tables, self-assessment questions, and a short bibliography of recommended reading. An essential resource for medical students, trainees, and other medical professionals seeking a clear and comprehensive introduction to psychiatry.
The concept of dignity is core to community district nursing practice, yet it is profoundly complex with multiple meanings and interpretations. Dignity does not exist absolutely, but, rather, becomes socially (de)constructed through and within social interactions between nurses and older adult patients in relational aspects of care. It is a concept, however, which has, to date, received little attention in the context of the community nursing care of older adults. Previous research into dignity in health care has often focused on care within institutional environments, very little, however, explores the variety of ways in which dignity is operationalised in community settings where district nursing care is conducted ‘behind closed doors’, largely free from the external gaze. This means dignity (or the lack of it) may go unobserved in community settings. Drawing on observational and interview data, this paper highlights the significance of dignity for older adults receiving nursing care in their own homes. We will demonstrate, in particular, how dignity manifests within the relational aspects of district nursing care delivery and how tasks involving bodywork can be critical to the ways in which dignity is both promoted and undermined. We will further highlight how micro-articulations in caring relationships fundamentally shape the ‘dignity encounter’ through a consideration of the routine and, arguably, mundane aspects of community district nursing care in the home.
The remnant phase of a radio galaxy begins when the jets launched from an active galactic nucleus are switched off. To study the fraction of radio galaxies in a remnant phase, we take advantage of a $8.31$ deg$^2$ subregion of the GAMA 23 field which comprises of surveys covering the frequency range 0.1–9 GHz. We present a sample of 104 radio galaxies compiled from observations conducted by the Murchison Widefield Array (216 MHz), the Australia Square Kilometer Array Pathfinder (887 MHz), and the Australia Telescope Compact Array (5.5 GHz). We adopt an ‘absent radio core’ criterion to identify 10 radio galaxies showing no evidence for an active nucleus. We classify these as new candidate remnant radio galaxies. Seven of these objects still display compact emitting regions within the lobes at 5.5 GHz; at this frequency the emission is short-lived, implying a recent jet switch off. On the other hand, only three show evidence of aged lobe plasma by the presence of an ultra-steep-spectrum ($\alpha<-1.2$) and a diffuse, low surface brightness radio morphology. The predominant fraction of young remnants is consistent with a rapid fading during the remnant phase. Within our sample of radio galaxies, our observations constrain the remnant fraction to $4\%\lesssim f_{\mathrm{rem}} \lesssim 10\%$; the lower limit comes from the limiting case in which all remnant candidates with hotspots are simply active radio galaxies with faint, undetected radio cores. Finally, we model the synchrotron spectrum arising from a hotspot to show they can persist for 5–10 Myr at 5.5 GHz after the jets switch of—radio emission arising from such hotspots can therefore be expected in an appreciable fraction of genuine remnants.
The rise of multi-party processes in which people with quite different ties to a region, natural resource-related industry, or environmental issue work collaboratively to hammer out mutually acceptable agreements is arguably one of the biggest shifts in environmental management over the past twenty-five years. This chapter engages in some sensemaking around this diverse and evolving phenomenon in two ways. First, an approach to designing collaborative natural resource-related discourse with a particularly strong theoretical foundation (Collaborative Learning) is presented to illustrate how theory is manifest in practice. Second a recent best practices/common features list is examined through the perspectives of four social science theorists: Max Weber, Pierre Bourdieu, Niklas Luhmann, and Muzafer Sherif. The practical recommendations that emerge from this list is largely consistent with the larger social and communicative dynamics articulated by these theorists.
In 1900, a syndicate of investors used open market purchases and manipulative trading strategies to exploit an ongoing financial crisis at the Third Avenue Railroad Company and stealthily gain control of the company. The acquisition occurred during the first great merger wave in U.S. history and represented the street railway industry’s response to a new technology, namely electrification. The lax regulatory environment of the period allowed operators and insiders to profit handsomely and may have benefited consumers, but possibly harmed some minority shareholders. Our case study illuminates an unusual acquisition, when capital markets were less transparent.
We present a calibration component for the Murchison Widefield Array All-Sky Virtual Observatory (MWA ASVO) utilising a newly developed PostgreSQL database of calibration solutions. Since its inauguration in 2013, the MWA has recorded over 34 petabytes of data archived at the Pawsey Supercomputing Centre. According to the MWA Data Access policy, data become publicly available 18 months after collection. Therefore, most of the archival data are now available to the public. Access to public data was provided in 2017 via the MWA ASVO interface, which allowed researchers worldwide to download MWA uncalibrated data in standard radio astronomy data formats (CASA measurement sets or UV FITS files). The addition of the MWA ASVO calibration feature opens a new, powerful avenue for researchers without a detailed knowledge of the MWA telescope and data processing to download calibrated visibility data and create images using standard radio astronomy software packages. In order to populate the database with calibration solutions from the last 6 yr we developed fully automated pipelines. A near-real-time pipeline has been used to process new calibration observations as soon as they are collected and upload calibration solutions to the database, which enables monitoring of the interferometric performance of the telescope. Based on this database, we present an analysis of the stability of the MWA calibration solutions over long time intervals.
Cerebral white matter changes (WMC) represent cerebrovascular disease (CVD) and are common in dementia. Cholinesterase inhibitors (ChEIs) are effective in Alzheimer's Disease (AD) with or without CVD, and in Dementia with Lewy Bodies/Parkinson's Disease Dementia (DLB/PDD). Predictors of treatment response are controversial.
Objective:
To investigate the effect of WMC severity on response to ChEIs in dementia.
Method:
CT or MRI brain scans were rated for WMC severity in 243 patients taking ChEIs for dementia. Raters were blind to patients' clinical risk factors, dementia subtype and course of illness. Effects of WMC severity on rates of decline in cognition, function and behaviour were analysed for 140 patients treated for nine months or longer. Analysis was performed for this group as a whole and within diagnostic subgroups AD and DLB/PDD. The main outcome measure was rate of change in Mini Mental State Examination (MMSE) score. Secondary measures were rates of change in scores on the Cambridge Cognitive Examination (CAMCOG), Instrumental Activities of Daily Living (IADL) and Clifton Assessment Procedures for the Elderly – Behaviour Rating Scale (CAPE-BRS).
Results:
There was no significant correlation between severity of WMC and any specified outcome variable for the cohort as a whole or for patients with AD. In patients with DLB/PDD, higher WMC scores were associated with more rapid cognitive decline.
Conclusions:
Increased WMC severity does not predict response to ChEIs in AD, but may weaken response to ChEIs in patients with DLB/PDD.
The primary objective of this study was to examine the impact of an electronic medical record (EMR)–driven intensive care unit (ICU) antimicrobial stewardship (AMS) service on clinician compliance with face-to-face AMS recommendations. AMS recommendations were defined by an internally developed “5 Moments of Antimicrobial Prescribing” metric: (1) escalation, (2) de-escalation, (3) discontinuation, (4) switch, and (5) optimization. The secondary objectives included measuring the impact of this service on (1) antibiotic appropriateness, and (2) use of high-priority target antimicrobials.
Methods:
A prospective review was undertaken of the implementation and compliance with a new ICU-AMS service that utilized EMR data coupled with face-to-face recommendations. Additional patient data were collected when an AMS recommendation was made. The impact of the ICU-AMS round on antimicrobial appropriateness was evaluated using point-prevalence survey data.
Results:
For the 202 patients, 412 recommendations were made in accordance with the “5 Moments” metric. The most common recommendation made by the ICU-AMS team was moment 3 (discontinuation), which comprised 173 of 412 recommendations (42.0%), with an acceptance rate of 83.8% (145 of 173). Data collected for point-prevalence surveys showed an increase in prescribing appropriateness from 21 of 45 (46.7%) preintervention (October 2016) to 30 of 39 (76.9%) during the study period (September 2017).
Conclusions:
The integration of EMR with an ICU-AMS program allowed us to implement a new AMS service, which was associated with high clinician compliance with recommendations and improved antibiotic appropriateness. Our “5 Moments of Antimicrobial Prescribing” metric provides a framework for measuring AMS recommendation compliance.
The first ultraviolet photochemical oxidation (UVox) extraction method for marine dissolved organic carbon (DOC) as CO2 gas was established by Armstrong and co-workers in 1966. Subsequent refinement of the UVox technique has co-evolved with the need for high-precision isotopic (Δ14C, δ13C) analysis and smaller sample size requirements for accelerator mass spectrometry radiocarbon (AMS 14C) measurements. The UVox line at UC Irvine was established in 2004 and the system reaction kinetics and efficiency for isolating seawater DOC rigorously tested for quantitative isolation of ∼1 mg C for AMS 14C measurements. Since then, improvements have been made to sampling, storage, and UVox methods to increase overall efficiency. We discuss our progress, and key UVox system parameters for optimizing precision, accuracy, and efficiency, including (1) ocean to reactor: filtration, storage and preparation of DOC samples, (2) cryogenic trap design, efficiency and quantification of CO2 break through, and (3) use of isotopic standards, blanks and small sample graphitization techniques for the correction of DOC concentrations and Fm values with propagated uncertainties. New DOC UVox systems are in use at many institutions. However, rigorous assessment of quantitative UVox DOC yields and blank contributions, DOC concentrations and carbon isotopic values need to be made. We highlight the need for a community-wide inter-comparison study.
We describe the motivation and design details of the ‘Phase II’ upgrade of the Murchison Widefield Array radio telescope. The expansion doubles to 256 the number of antenna tiles deployed in the array. The new antenna tiles enhance the capabilities of the Murchison Widefield Array in several key science areas. Seventy-two of the new tiles are deployed in a regular configuration near the existing array core. These new tiles enhance the surface brightness sensitivity of the array and will improve the ability of the Murchison Widefield Array to estimate the slope of the Epoch of Reionisation power spectrum by a factor of ∼3.5. The remaining 56 tiles are deployed on long baselines, doubling the maximum baseline of the array and improving the array u, v coverage. The improved imaging capabilities will provide an order of magnitude improvement in the noise floor of Murchison Widefield Array continuum images. The upgrade retains all of the features that have underpinned the Murchison Widefield Array’s success (large field of view, snapshot image quality, and pointing agility) and boosts the scientific potential with enhanced imaging capabilities and by enabling new calibration strategies.
We describe the design and performance of the Engineering Development Array, which is a low-frequency radio telescope comprising 256 dual-polarisation dipole antennas working as a phased array. The Engineering Development Array was conceived of, developed, and deployed in just 18 months via re-use of Square Kilometre Array precursor technology and expertise, specifically from the Murchison Widefield Array radio telescope. Using drift scans and a model for the sky brightness temperature at low frequencies, we have derived the Engineering Development Array’s receiver temperature as a function of frequency. The Engineering Development Array is shown to be sky-noise limited over most of the frequency range measured between 60 and 240 MHz. By using the Engineering Development Array in interferometric mode with the Murchison Widefield Array, we used calibrated visibilities to measure the absolute sensitivity of the array. The measured array sensitivity matches very well with a model based on the array layout and measured receiver temperature. The results demonstrate the practicality and feasibility of using Murchison Widefield Array-style precursor technology for Square Kilometre Array-scale stations. The modular architecture of the Engineering Development Array allows upgrades to the array to be rolled out in a staged approach. Future improvements to the Engineering Development Array include replacing the second stage beamformer with a fully digital system, and to transition to using RF-over-fibre for the signal output from first stage beamformers.
Land hermit crabs (Coenobitidae) are widespread and abundant in Recent tropical and subtropical coastal environments, yet little is known about their fossil record. A walking trace, attributed to a land hermit crab, is described herein as Coenobichnus currani (new ichnogenus and ichnospecies). This trace fossil occurs in an early Holocene eolianite deposit on the island of San Salvador, Bahamas. The fossil trackway retains the distinctive right and left asymmetry and interior drag trace that are diagnostic of modern land hermit crab walking traces. The overall size, dimensions and shape of the fossil trackway are similar to those produced by the modem land hermit crab, Coenobita clypeatus, which occurs in the tropical western Atlantic region. The trackway was compared to other arthropod traces, but it was found to be distinct among the arthropod traces described from dune or other environments. The new ichnogenus Coenobichnus is proposed to accommodate the asymmetry of the trackway demarcated by left and right tracks. The new ichnospecies Coenobichnus currani is proposed to accommodate the form of the proposed Coenobichnus that has a shell drag trace.