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Background Infection with parasitic nematodes (helminths), particularly those of the order Strongylida (such as Haemonchus contortus ), can cause significant and burdensome diseases in humans and animals. Widespread drug (anthelmintic) resistance in livestock parasites, the absence of vaccines against most of these nematodes, and a lack of new and effective chemical entities on the commercial market demands the discovery of new anthelmintics. In the present study, we searched the Global Health Priority Box (Medicines for Malaria Venture) for new candidates for anthelmintic development. Methods We employed a whole-organism, motility-based phenotypic screening assay to identify compounds from the Global Health Priority Box with activity against larvae of the model parasite H. contortus , and the free-living comparator nematode Caenorhabditis elegans . Hit compounds were further validated via dose–response assays, with lead candidates then assessed for nematocidal activity against H. contortus adult worms, and additionally, for cytotoxic and mitotoxic effects on human hepatoma (HepG2) cells. Results The primary screen against H. contortus and C. elegans revealed or reidentified 16 hit compounds; further validation established MMV1794206, otherwise known as ‘flufenerim’, as a significant inhibitor of H. contortus larval motility (half-maximal inhibitory concentration [IC 50 ] = 18 μM) and development (IC 50  = 1.2 μM), H. contortus adult female motility (100% after 12 h of incubation) and C. elegans larval motility (IC 50  = 0.22 μM). Further testing on a mammalian cell line (human hepatoma HepG2 cells), however, identified flufenerim to be both cytotoxic (half-maximal cytotoxic concentration [CC 50 ] < 0.7 μM) and mitotoxic (half-maximal mitotoxic concentration [MC 50 ] < 0.7 μM). Conclusions The in vitro efficacy of MMV1794206 against the most pathogenic stages of H. contortus , as well as the free-living C. elegans , suggests the potential for development as a broad-spectrum anthelmintic compound; however, the high toxicity towards mammalian cells presents a significant hindrance. Further work should seek to establish the protein–drug interactions of MMV1794206 in a nematode model, to unravel the mechanism of action, in addition to an advanced structure–activity relationship investigation to optimise anthelmintic activity and eliminate mammalian cell toxicity. Graphical Abstract

Parasitic nematodes cause diseases in livestock animals and major economic losses to the agricultural industry worldwide. Nematodes of the order Strongylida, including Haemonchus contortus, are particularly important. The excessive use of anthelmintic compounds to treat infections and disease has led to widespread resistance to these compounds in nematodes, such that there is a need for new anthelmintics with distinctive mechanisms of action. With a focus on discovering new anthelmintic entities, we screened 400 chemically diverse compounds within the ‘Pandemic Response Box’ (from Medicines for Malaria Venture, MMV) for activity against H. contortus and its free-living relative, Caenorhabditis elegans—a model organism. Using established phenotypic assays, test compounds were evaluated in vitro for their ability to inhibit the motility and/or development of H. contortus and C. elegans. Dose-response evaluations identified a compound, MMV1581032, that significantly the motility of H. contortus larvae (IC50 = 3.4 ± 1.1 μM) and young adults of C. elegans (IC50 = 7.1 ± 4.6 μM), and the development of H. contortus larvae (IC50 = 2.2 ± 0.7 μM). The favourable characteristics of MMV1581032, such as suitable physicochemical properties and an efficient, cost-effective pathway to analogue synthesis, indicates a promising candidate for further evaluation as a nematocide. Future work will focus on a structure-activity relationship investigation of this chemical scaffold, a toxicity assessment of potent analogues and a mechanism/mode of action investigation.

IntroductionAnalyse whether Heartflow (HF) has decreased downstream testing in our hospital compared to our previous standard practice based on CADRADS/NICE guidance, along with accuracy of CTFFR compared to invasive pressure wire study( FFR).MethodsRetrospective analysis of 184 patients with new onset stable chest pain undergone CTFFR (CADRADS 3-5) from September 2021- June 2023.CTFFR accuracy results were evaluated by comparing them with invasive FFR (FFR<0.80).ResultsDownstream testsHF positive (n=46): 5 invasive diagnostic angiography (ICA),31 percutaneous coronary intervention( PCI) ,3 awaiting ICA, 2 stress CMRI ,1 stress echo, 2 awaiting stress CMRI and 2/46(4.3%) had no further tests.HF indeterminate(n=30): 4 ICA,9 had PCI, 3 stress echo, 1 exercise tolerance test(ETT), 2 awaiting ICA, 1 awaiting CMRI and 10/30 (33.3%) had no further tests.HF negative(n=108): 7 ICA , 5 had PCI , 3 awaiting ICA, 3 stress CMRI , 1 stress echo, 1 ETT ,1 MPS, 1 awaiting stress CMRI, 3 awaiting echo and 83/108(76%) had no further tests.CTFFR VS FFR: 31/184(16%) patients had subsequent Invasive FFR, 26/31(83%) FFR was equivalent to the CTFFR and 5/31(16%) invasive FFR was different to the CTFFR(3 CTFFR were positive while invasive FFR was negative and 2 CTFFR were negative while invasive FFR was positive).ConclusionHF has significantly reduced our need for downstream testing in the CTCA population. A total of 76% of patients in HF negative group did not have any further tests.In addition, there was high sensitivity of CTFFR when compared to invasive FFR.

IntroductionTo describe ANP role within current CTCA service, including administering beta-blockade, and future progression to ANP-led CTCA listsMethodsOur CTCA service started in 2015 with a Cardiologist/Radiologist, 2 radiographers and 1 ANP per list, and expanded with updated stable chest pain NICE guideline (CG95) 2016. At CTCA the ANP administers rate control up to a total of 50mg IV Metoprolol and GTN. We formally agreed a betablockade protocol and referrals detail drug suitability. The ANP has access to patient notes and collaborative decision-making support within the team. The ANP must have Advanced Life Support Provider qualification to support lists. The ANP role also includes history taking, diagnosis and treatment of patients with potential cardiac disease including patients with chest pain. ANPs request investigations and prescribe pre-procedural rate control medication. ANPs interpret reported findings and commence appropriate treatment. Satisfaction questionnaires were obtained from patients alongside regular audit of CTCA service. Standardisation of the service was met with clear pharmaceutical protocols and referral guidelines.ResultsData from local audit has highlighted positive CTCA outcomes and high level of patient satisfaction. This supported expansion of the service, including team, lists and advancing technologies. The ANP-led service has freed up consultant time for reporting.ConclusionANP-led patient care and drug administration at CTCA improves continuity of care for patients, provides efficient team structure for supporting cardiac imaging and facilitates consultant reporting time. Fully ANP-led lists with our new scanners in 2024 should reduce ongoing service costs and further increase consultant reporting time.

IntroductionNICE Guidance (CG95 and MTG32) recommends FFR-CT for the investigation of stable angina. It acts as a gatekeeper to reduce the number of patients from undergoing potentially unnecessary invasive coronary angiography(ICA) and intervention(PCI) even in the presence of moderate or significant anatomical disease but normal FFRCT value.AimAnalyse whether Heartflow (HF)has decreased downstream testing in our hospital compared to our previous standard practice based on CADRADS/NICE guidance.Additionally, we looked at the ability of CTFFR in the CADRADS 3 group in predicting future events along with accuracy of CTFFR compared to invasive FFR or other functional tests.MethodsRetrospective analysis of 117 consecutive patients with suspected symptomatic coronary artery disease undergoing CT FFR from September 2021- December 2022.Follow up data included down streaming tests in all groups and calculation of major adverse cardiovascular and cerebrovascular events ( stroke, fatal or nonfatal myocardial infarction, cardiovascular death) and revascularization (PCI or CABG) in the CADRADS 3 patient group.Diagnostic accuracy of CTFFR results were evaluated by comparing them with invasive pressure wire study (PWS) (FFR<0.80) or indirectly by functional testingResultsAmong 117 cases sent for Heart flow, 114 patients were in CAD RADS 3-5 and 3 patients in CAD RADS 2.Downstream tests: Invasive FFR/ angiography and non-invasive testingCADRADS 4/5 group:Heart flow positive (n=29): 28/29 (96%) patients either undergone or currently awaiting ICA+/-PCI , 1 patient had negative stress CMRI.Heart flow indeterminate (n=5): 2 patient had ICA only, 2 had stress echo and 1 patient had negative exercise tolerance test.Heart flow negative (n=16): 6/16 (37%) patients either undergone or currently awaiting ICA+/-PCI, 1/16 patient had negative stress CMRI and 9/16(56%) patients did not have any further downstream tests.CADRADS 3 group:Heart flow positive(n=7): 5/7 (71%) patients had ICA +/-PCI procedure, 1/7 (14%) had stress CMRI and 1/7 (14%) did not have any further testing based on symptoms.Indeterminate group(n=8): 4/8 (50%) patients had ICA+/- PCI and 4/8 (50%) patients did not have any further tests after symptom review.Heart flow negative (n=49): 3/49(6.1%) patients either undergone or currently awaiting ICA+/-PCI, 4/49 (8%) patient had functional tests and 42/49 (85%) patients did not have any further testsCTFFR VS FFR13/117(11%) patients had subsequent PWS with adenosine.10/13(78%) patient FFR was similar to CTFFR and 3 /13 (22%)FFR was different reading than CTFFR.36/117 (30%) patients had down stream testing of either CMRI, MPS, ETT, angiogram or direct stenting to corresponding vessel, all 36/36 (100%) was correlated to CTFFR measures reading. Combining accuracy of CTFFR compare to both invasive FFR and functional tests was 46/49 (94%).Major adverse cardiovascular event in CADRADS 3 groupNo MACCE event reported for up to 16 months follow up in this group.ConclusionHeartflow has significantly reduced our need for downstream testing in the CTCA population. Of the CTFFR negative group, 51/117 (43%) of patients did not need any further tests who would have previously needed further testing when CT FFR was previously unavailable.In addition, there was high sensitivity of CTFFR when compared to either pressure wire study or functional ischemia testing. In short term follow up, none of the patients in the CADRADS 3 group had any MACCE.Abstract 187 Figure 1Flow chart of CTFFR negative patients in all CADRADS groups(3-5) with down streaming tests vs no further testsAbstract 187 Table 1Down streaming tests distribution among different CADRADS category, functional tests includes stress CMRI, stress ECHO, MPS and ETT CADRADS group Functional tests Invasive coronary angiogram/PCI No further test CADRADS 4/5 negative (n=16)169Indeterminate (n5)320Positive(n29)1280CADRADS 3 negative (n49)4342Indeterminate (n=8)044Positive (n=7)151Conflict of Interestnone

Chemokines play an important role during granulomatous inflammation in murine models of Schistosoma mansoni infection. Here, the expression and possible roles of chemokines during human S. mansoni infection were examined. Compared with uninfected individuals, infected patients had elevated plasma concentrations of macrophage inflammatory protein (MIP)–1α, RANTES (regulated on activation, normally T cell–expressed and secreted), and eotaxin. Concentrations of macrophage-derived chemokine, eotaxin-2, monocyte chemotactic protein–1, growth-related oncogene, and interleukin-8 were similar between the 2 groups. When subjects were grouped according to disease severity, individuals with a plasma MIP-1α concentration >400 pM had a 10-times greater risk of having the more severe hepatosplenic form of disease. In the in vitro granuloma reaction, greater concentrations of MIP-1α were produced by cells of patients with hepatosplenic disease than cells of patients with intestinal disease. Pretreatment with a chemokine receptor antagonist attenuated the enhanced in vitro reaction seen with cells derived from patients with hepatosplenic disease. MIP-1α may not only mark a subset of patients with a greater risk of having more severe disease but also play a relevant pathophysiological role in human schistosomiasis

ContextFire behaviour research has largely focused on dry ecosystems that burn frequently, with far less attention on wetter forests. Yet, the impacts of fire in wet forests can be high and therefore understanding the drivers of fire in these systems is vital.ObjectivesWe sought to identify and rank by importance the factors plausibly driving flammability in wet eucalypt forests, and describe relationships between them. In doing so, we formulated a set of research priorities.MethodsConceptual models of forest flammability in wet eucalypt forests were elicited from 21 fire experts using a combination of elicitation techniques. Forest flammability was defined using fire occurrence and fireline intensity as measures of ignitability and heat release rate, respectively.ResultsThere were shared and divergent opinions about the drivers of flammability in wet eucalypt forests. Widely agreed factors were drought, dead fine fuel moisture content, weather and topography. These factors all influence the availability of biomass to burn, albeit their effects and interactions on various dimensions of flammability are poorly understood. Differences between the models related to lesser understood factors (e.g. live and coarse fuel moisture, plant traits, heatwaves) and the links between factors.ConclusionsBy documenting alternative conceptual models, we made shared and divergent opinions explicit about flammability in wet forests. We identified four priority research areas: (1) quantifying drought and fuel moisture thresholds for fire occurrence and intensity, (2) modelling microclimate in dense vegetation and rugged terrain, (3) determining the attributes of live vegetation that influence forest flammability, (4) evaluating fire management strategies.

Preservice teachers generally are confident and enthusiastic about their abilities to teach effectively. These desirable qualities are based, for the most part, on the preservice teachers' previous experiences as students in the classroom, not as teachers. While the personal experience a preservice teacher brings to his or her teacher-preparation program represents an important foundation for professional growth, the role as an instructional leader in the classroom is one that must be learned. Learning to teach occurs in varied settings in most university teacher-education programs. The process of learning to teach in the classroom of another teacher typically produces excellent results. The dynamics of entering another teacher's classroom, however, requires sensitivity, patience, and flexibility in this mentoring relationship. Preservice teachers, as guests in the classroom of the cooperating teachers, are best received when they adhere to specific etiquette. In this article, the authors share tips for preservice teachers entering the classrooms of cooperating teachers. These tips are based on their experiences, observations, and feedback gained as university site professors through a partnership with a local high school.

The United States Air Force Academy (USAFA) is one of the nation's military universities, with the mission to educate and motivate cadets to be career Air Force officers. This diverse population arrives at the USAFA with varying immunization records and disease histories. A review of USAFA cadet medical records identified an alarming cost of treating a simple, preventable, generally childhood disease: chickenpox. In July 1995, a cost-benefit analysis was performed on the use of varicella vaccine among cadets and preparatory school students at the USAFA. Based on this analysis, the USAFA implemented a strategy of serologic screening and vaccination. Although this study does not establish causation, follow-up data showed a dramatic decrease in cases, associated hospitalizations, and therefore costs during the first year after implementation. Fiscal projections indicate that these costs savings should increase through year 4 of the program and continue thereafter. At year 4, the total cadet population will have been serologically screened and/or vaccinated against chickenpox.