Qualitative study of primary care clinicians\u27 views on point-of-care testing for C-reactive protein for acute respiratory tract infections in family medicine.

OBJECTIVE: To explore clinicians views of the barriers and facilitators to use of C-reactive protein (CRP) point-of-care tests (POCT) in US family medicine clinics for the management of acute respiratory tract infections (ARTIs) in adults. SETTING: Five family medicine clinics across two US states. PARTICIPANTS: 30 clinicians including 18 physicians, 9 physician residents, 2 physician assistants and 1 nurse practitioner, took part in the study. DESIGN: A qualitative study using a grounded theory approach to thematically analyse focus group interviews. RESULTS: These clinicians had limited access to diagnostic tests for patients with ARTI, and very little knowledge of CRP POCT. Three major themes were identified and included the potential clinical role of CRP POCT, concerns related to implementing CRP POCT and evidence needed prior to wider adoption in family medicine. Clinicians believed CRP POCT could support decision-making for some presentations of ARTIs and patient populations when used in conjunction with clinical criteria. Clinicians had concerns about possible overuse and inaccuracy of CRP POCT which they believed might increase antibiotic prescribing rates. Other concerns identified included integration of the test with clinic workflows and cost-effectiveness. CONCLUSIONS: Clinicians stand at the forefront of antibiotic stewardship efforts, but have few diagnostic tests to help them confidently manage ARTIs. CRP POCT may facilitate some aspects of clinical practice. Incorporating CRP POCT with clinical guidelines may strengthen utility of this test, when there is diagnostic uncertainty

Patient Willingness to Have Tests to Guide Antibiotic Use for Respiratory Tract Infections: From the WWAMI Region Practice and Research Network (WPRN).

INTRODUCTION: The majority of consultations for acute respiratory tract infections (RTIs) lead to prescriptions for antibiotics, which have limited clinical benefit. We explored patients' willingness to have blood tests as part of the diagnostic work-up for RTIs, and patient knowledge about antibiotics. METHODS: Patients at 6 family medicine clinics were surveyed. Regression modeling was used to determine independent predictors of willingness to have venous and point-of-care (POC) blood tests, and knowledge of the value of antibiotics for RTIs. RESULTS: Data were collected from 737 respondents (response rate 83.8%), of whom 65.7% were women, 60.1% were white, and 25.1% were current smokers; patients' mean age was 46.9 years. Sex (female), race (white), and a preference to avoid antibiotics were independent predictors of greater level of antibiotic knowledge. A total of 63.1% were willing to have a venous draw and 79% a POC blood test, to help guide antibiotic decision-making. Non-American Indian/Alaskan Native race, current smoking, and greater knowledge of antibiotics were independent predictors of willingness to have a POC test. CONCLUSION: A large majority of patients seemed willing to have POC tests to facilitate antibiotic prescribing decisions for RTIs. Poor knowledge about antibiotics suggests better education regarding antibiotic use might influence patient attitudes towards use of antibiotics for RTIs

Postcolonial town planning in Commonwealth nations: A case study of the Solomon Islands - an agenda for change

This is the author's PDF version of an article published in The Round Table: The Commonwealth Journal of International Affairs© 2007. The definitive version is available at www.informaworld.comThe principal argument advanced in this paper is that spatial planning in the Solomon Islands has failed to deliver any substantive benefits and is therefore in urgent need of reform. The present model of planning, derived from a combination of colonial practice and legislation originating in the UK, does not add much, if any, value to the development process. The poor quality of planning in the Solomons cannot be seen in isolation. There are similar systems in use throughout much of the Commonwealth and anecdotal evidence suggests that the failings are widely duplicated. The Solomon Islands only appear exceptional in the extent to which other government systems have demonstrably broken down, following the 'Ethnic Tension' of 2000 - 03. The Regional Assistance Mission to the Solomon Islands (RAMSI) provides a unique opportunity for a review of the way in which planning operates. A number of issues are identified which any reformed system must address

Scallop potting with lights : a novel, low impact method for catching European king scallop (Pecten maximus)

This paper describes, for the first time, that scallops can be attracted into static fishing gear using LED lights. This novel finding presents an opportunity for the development of a new, low impact fishing method for scallops. Traditionally, wild caught scallops are primarily fished using dredges and trawls. Due to their penetrative nature, the interaction of this towed gear with the seabed can cause significant damage to sensitive marine habitats and species. Diver caught scallops have been a low impact alternative source, however, this sector can only supply limited quantities due to logistical constraints. In this study, we investigate the potential for scallops to be fished using illuminated standard commercial crustacean pots. We assessed the effect of using light in a range of pot designs on scallop, brown crab, lobster and crawfish, and spider crab catches in Cornwall between December 2020 and February 2021. A total of 77 strings were shot, deploying 1886 pots of six treatment types. The fishing grounds used in the trial are traditionally potted for crustacea and are not renowned scallop beds. Despite this, all treatments with lights retained scallops and of the 518 scallops recorded, 99.6% (n = 516) were caught in pots with lights. A modified parlour pot with lights (treatment F) caught scallops most effectively, with a maximum catch rate of 19 scallops per string (23–24 pots per string) per 24-, and the maximum number of scallops recorded in a single pot was 24. We show that simple and inexpensive modifications to existing crustacean pots present fishers the opportunity to augment their existing crustacean catches with a low environmental impact, premium scallop product. Further refinement to pot design and the lights are needed to enhance scallop and crustacean retention before a commercially viable fishery can be established. We discuss the opportunities that these new findings present to the fishing industry and marine managers

The expansion asymmetry and age of the Cassiopeia A supernova remnant

HST images of the young supernova remnant Cas A are used to explore the expansion and spatial distribution of its highest velocity debris. ACS WFC images taken in 2004 March and December with Sloan F625W, F775W, and F850LP filters were used to identify 1825 high-velocity, outlying ejecta knots through measured proper motions of 0."35 - 0."90 yr(-1), corresponding to V-trans = 5500-14,500 km s(-1) assuming d = 3.4 kpc. The distribution of derived transverse expansion velocities for these ejecta knots shows a striking bipolar asymmetry with the highest velocity knots (V-trans >= 10,500 km s(-1)) confined to nearly opposing northeast and southwest "jets'' at P.A. = 45 degrees-70 degrees and 230 degrees-270 degrees, respectively. The jets have about the same maximum expansion velocity of similar or equal to 14,000 km s(-1) and appear kinematically and chemically distinct in that they are the remnant's only S-rich ejecta with expansion velocities above the 10,000-11,000 km s(-1) exhibited by outer nitrogen-rich ejecta, which otherwise represent the remnant's highest velocity debris. In addition, we find significant gaps in the spatial distribution of outlying ejecta in directions that are approximately perpendicular to the jets (P.A. = 145 degrees-200 degrees and 335 degrees-350 degrees). The remnant's central X-ray point source lies some 700 to the southeast of the estimated expansion center ( P.A. = 169 degrees +/- 8.degrees 4) indicating a projected motion toward the middle of the broad southern ejecta knot gap. Extrapolations of measured 9 month proper motions for all 1825 outer ejecta knots and a selected subsample of 72 bright and compact knots suggest explosion dates (assuming no knot deceleration) of 1662 +/- 27 and 1672 +/- 18, respectively. We find some evidence for nonuniform deceleration in different directions around the remnant and find 126 knots located along the northwestern limb among the least decelerated ejecta, suggesting a convergence date of 1681 +/- 19. A remnant age of around 325 yr would imply a +/- 350 km s(-1) transverse velocity for the central X-ray point source

Gauging NOTCH1 Activation in Cancer Using Immunohistochemistry

Fixed, paraffin-embedded (FPE) tissues are a potentially rich resource for studying the role of NOTCH1 in cancer and other pathologies, but tests that reliably detect activated NOTCH1 (NICD1) in FPE samples have been lacking. Here, we bridge this gap by developing an immunohistochemical (IHC) stain that detects a neoepitope created by the proteolytic cleavage event that activates NOTCH1. Following validation using xenografted cancers and normal tissues with known patterns of NOTCH1 activation, we applied this test to tumors linked to dysregulated Notch signaling by mutational studies. As expected, frequent NICD1 staining was observed in T lymphoblastic leukemia/lymphoma, a tumor in which activating NOTCH1 mutations are common. However, when IHC was used to gauge NOTCH1 activation in other human cancers, several unexpected findings emerged. Among B cell tumors, NICD1 staining was much more frequent in chronic lymphocytic leukemia than would be predicted based on the frequency of NOTCH1 mutations, while mantle cell lymphoma and diffuse large B cell lymphoma showed no evidence of NOTCH1 activation. NICD1 was also detected in 38% of peripheral T cell lymphomas. Of interest, NICD1 staining in chronic lymphocytic leukemia cells and in angioimmunoblastic lymphoma was consistently more pronounced in lymph nodes than in surrounding soft tissues, implicating factors in the nodal microenvironment in NOTCH1 activation in these diseases. Among carcinomas, diffuse strong NICD1 staining was observed in 3.8% of cases of triple negative breast cancer (3 of 78 tumors), but was absent from 151 non-small cell lung carcinomas and 147 ovarian carcinomas. Frequent staining of normal endothelium was also observed; in line with this observation, strong NICD1 staining was also seen in 77% of angiosarcomas. These findings complement insights from genomic sequencing studies and suggest that IHC staining is a valuable experimental tool that may be useful in selection of patients for clinical trials

Effects of S1 Cleavage on the Structure, Surface Export, and Signaling Activity of Human Notch1 and Notch2

Notch receptors are normally cleaved during maturation by a furin-like protease at an extracellular site termed S1, creating a heterodimer of non-covalently associated subunits. The S1 site lies within a key negative regulatory region (NRR) of the receptor, which contains three highly conserved Lin12/Notch repeats and a heterodimerization domain (HD) that interact to prevent premature signaling in the absence of ligands. Because the role of S1 cleavage in Notch signaling remains unresolved, we investigated the effect of S1 cleavage on the structure, surface trafficking and ligand-mediated activation of human Notch1 and Notch2, as well as on ligand-independent activation of Notch1 by mutations found in human leukemia.The X-ray structure of the Notch1 NRR after furin cleavage shows little change when compared with that of an engineered Notch1 NRR lacking the S1-cleavage loop. Likewise, NMR studies of the Notch2 HD domain show that the loop containing the S1 site can be removed or cleaved without causing a substantial change in its structure. However, Notch1 and Notch2 receptors engineered to resist S1 cleavage exhibit unexpected differences in surface delivery and signaling competence: S1-resistant Notch1 receptors exhibit decreased, but detectable, surface expression and ligand-mediated receptor activation, whereas S1-resistant Notch2 receptors are fully competent for cell surface delivery and for activation by ligands. Variable dependence on S1 cleavage also extends to T-ALL-associated NRR mutations, as common class 1 mutations display variable decrements in ligand-independent activation when introduced into furin-resistant receptors, whereas a class 2 mutation exhibits increased signaling activity.S1 cleavage has distinct effects on the surface expression of Notch1 and Notch2, but is not generally required for physiologic or pathophysiologic activation of Notch proteins. These findings are consistent with models for receptor activation in which ligand-binding or T-ALL-associated mutations lead to conformational changes of the NRR that permit metalloprotease cleavage

COVID-19 trajectories among 57 million adults in England: a cohort study using electronic health records

BACKGROUND: Updatable estimates of COVID-19 onset, progression, and trajectories underpin pandemic mitigation efforts. To identify and characterise disease trajectories, we aimed to define and validate ten COVID-19 phenotypes from nationwide linked electronic health records (EHR) using an extensible framework. METHODS: In this cohort study, we used eight linked National Health Service (NHS) datasets for people in England alive on Jan 23, 2020. Data on COVID-19 testing, vaccination, primary and secondary care records, and death registrations were collected until Nov 30, 2021. We defined ten COVID-19 phenotypes reflecting clinically relevant stages of disease severity and encompassing five categories: positive SARS-CoV-2 test, primary care diagnosis, hospital admission, ventilation modality (four phenotypes), and death (three phenotypes). We constructed patient trajectories illustrating transition frequency and duration between phenotypes. Analyses were stratified by pandemic waves and vaccination status. FINDINGS: Among 57 032 174 individuals included in the cohort, 13 990 423 COVID-19 events were identified in 7 244 925 individuals, equating to an infection rate of 12·7% during the study period. Of 7 244 925 individuals, 460 737 (6·4%) were admitted to hospital and 158 020 (2·2%) died. Of 460 737 individuals who were admitted to hospital, 48 847 (10·6%) were admitted to the intensive care unit (ICU), 69 090 (15·0%) received non-invasive ventilation, and 25 928 (5·6%) received invasive ventilation. Among 384 135 patients who were admitted to hospital but did not require ventilation, mortality was higher in wave 1 (23 485 [30·4%] of 77 202 patients) than wave 2 (44 220 [23·1%] of 191 528 patients), but remained unchanged for patients admitted to the ICU. Mortality was highest among patients who received ventilatory support outside of the ICU in wave 1 (2569 [50·7%] of 5063 patients). 15 486 (9·8%) of 158 020 COVID-19-related deaths occurred within 28 days of the first COVID-19 event without a COVID-19 diagnoses on the death certificate. 10 884 (6·9%) of 158 020 deaths were identified exclusively from mortality data with no previous COVID-19 phenotype recorded. We observed longer patient trajectories in wave 2 than wave 1. INTERPRETATION: Our analyses illustrate the wide spectrum of disease trajectories as shown by differences in incidence, survival, and clinical pathways. We have provided a modular analytical framework that can be used to monitor the impact of the pandemic and generate evidence of clinical and policy relevance using multiple EHR sources. FUNDING: British Heart Foundation Data Science Centre, led by Health Data Research UK

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant