Validation of an artificial intelligence solution for acute triage and rule-out normal of non-contrast CT head scans.

PURPOSE: Non-contrast CT head scans provide rapid and accurate diagnosis of acute head injury; however, increased utilisation of CT head scans makes it difficult to prioritise acutely unwell patients and places pressure on busy emergency departments (EDs). This study validates an AI algorithm to triage patients presenting with Intracranial Haemorrhage (ICH) or Acute Infarct whilst also identifying a subset of patients as Normal, with the potential to function as a rule-out test. METHODS: In total, 390 CT head scans were collected from 3 institutions in the UK, US and India. Ground-truth labels were assigned by 3 FRCR consultant radiologists. AI performance, as well as the performance of 3 independent radiologists, was measured against ground-truth labels. RESULTS: The algorithm showed AUC values of 0.988 (0.978-0.994), 0.933 (0.901-0.961) and 0.939 (0.919-0.958) for ICH, Acute Infarct and Normal, respectively. Sensitivity/specificity for ICH and Acute Infarct were 0.988/0.925 and 0.833/0.927, respectively, compared to 0.907/0.991 and 0.618/0.977 for radiologists. AI rule-out of Normal scans achieved 0.93% negative predictive value (NPV) for the removal of 54.3% of Normal cases, compared to 86.8% NPV for radiologists. CONCLUSION: We show our algorithm can provide effective triage of ICH and Acute Infarct to prioritise acutely unwell patients. AI can also benefit clinical accuracy, with the algorithm identifying 91.3% of radiologist false negatives for ICH and 69.1% for Acute Infarct. Rule-out of Normal scans has huge potential for workload management in busy EDs, in this case removing 27.4% of all scans with no acute findings missed.

Analysis of cross-resistance to Vip3 proteins in eight insect colonies, from four insect species, selected for resistance to Bacillus thuringiensis insecticidal proteins.

Bacillus thuringiensis Vip3 proteins are synthesized and secreted during the vegetative growth phase. They are activated by gut proteases, recognize and bind to midgut receptors, form pores and lyse cells. We tested the susceptibility to Vip3Aa and Vip3Ca of Cry1A-, Cry2A-, Dipel- and Vip3-resistant insect colonies from different species to determine whether resistance to other insecticidal proteins confers cross-resistance to Vip3 proteins. As expected, the colonies resistant to Cry1A proteins, Dipel (Helicoverpa armigera, Trichoplusia ni, Ostrinia furnacalis and Plodia interpunctella) or Cry2Ab (H. armigera and T. ni) were not cross-resistant to Vip3 proteins. In contrast, H. armigera colonies resistant to Vip3Aa or Vip3Aa/Cry2Ab showed cross-resistance to the Vip3Ca protein. Moreover, the Vip3Ca protein was highly toxic to O. furnacalis (LC50 not significantly different from that of Cry1Ab), whereas the Vip3Aa protein only showed moderate growth inhibition at the highest concentration tested (100 µg/g of diet). These results extend the cross-resistance studies between Vip3 and Cry proteins, show for the first time cross-resistance between proteins within the Vip3 subfamily, and points to O. furnacalis as a target for the Vip3Ca protein.

Histological features associated with diagnostic agreement in atypical ductal hyperplasia of the breast: illustrative cases from the B-Path study.

AIMS: This study examined the case-specific characteristics associated with interobserver diagnostic agreement in atypical ductal hyperplasia (ADH) of the breast. METHODS AND RESULTS: Seventy-two test set cases with a consensus diagnosis of ADH from the B-Path study were evaluated. Cases were scored for 17 histological features, which were then correlated with the participant agreement with the consensus ADH diagnosis. Participating pathologists' perceptions of case difficulty, borderline features or whether they would obtain a second opinion were also examined for associations with agreement. Of the 2070 participant interpretations of the 72 consensus ADH cases, 48% were scored by participants as difficult and 45% as borderline between two diagnoses; the presence of both of these features was significantly associated with increased agreement (P < 0.001). A second opinion would have been obtained in 80% of interpretations, and this was associated with increased agreement (P < 0.001). Diagnostic agreement ranged from 10% to 89% on a case-by-case basis. Cases with papillary lesions, cribriform architecture and obvious cytological monotony were associated with higher agreement. Lower agreement rates were associated with solid or micropapillary architecture, borderline cytological monotony, or cases without a diagnostic area that was obvious on low power. CONCLUSIONS: The results of this study suggest that pathologists frequently recognize the challenge of ADH cases, with some cases being more prone to diagnostic variability. In addition, there are specific histological features associated with diagnostic agreement on ADH cases. Multiple example images from cases in this test set are provided to serve as educational illustrations of these challenges.

A journey from basic stem cell discovery to clinical application: the case of adventitial progenitor cells.

Ischemia is a leading cause of death in the western world. Regenerative medicine aims to improve healing of ischemic injury by complementing pharmacologic/interventional treatments. Navigating regenerative therapies from 'bench-to-bedside' is a multistep time-consuming process, balancing cell expansion, purity, safety and efficacy while complying with regulatory guidelines. Studies started in academic laboratories unused to long-term planning often fail because of poor strategy design, lack of contingency plans or funding. We provide a strategic insight into our translation of saphenous vein-derived adventitial progenitor cells into a clinical grade product to treat angina. We discuss discovery phases, introduction of standard operating procedures and upgrade to clinical standards. We also examine contractual aspects of transferring to GMP-accredited facilities for clinical production and unexpected hurdles.

Electronic palliative care co-ordination system: an electronic record that supports communication for end-of-life care - a pilot in Richmond, UK.

Most people prefer to die at home, however, the majority die in an acute hospital. Supporting a patient in their preferred place of care may be aided by exchange of information across sectors. Richmond piloted an electronic palliative care coordination system (EPaCCS) to enhance interprofessional communication for end-of-life care. One such EPaCCS is the Coordinate My Care (CMC) hosted by the Royal Marsden NHS Foundation Trust, now supported across London. It focused clinicians on having advance care planning conversations with patients and their carers and then documenting the outcome onto an electronic web-based record that can be shared with key healthcare professionals.

Electronic palliative care co-ordination system: an electronic record that supports communication for end-of-life care - a pilot in Richmond, UK.

Most people prefer to die at home, however, the majority die in an acute hospital. Supporting a patient in their preferred place of care may be aided by exchange of information across sectors. Richmond piloted an electronic palliative care coordination system (EPaCCS) to enhance interprofessional communication for end-of-life care. One such EPaCCS is the Coordinate My Care (CMC) hosted by the Royal Marsden NHS Foundation Trust, now supported across London. It focused clinicians on having advance care planning conversations with patients and their carers and then documenting the outcome onto an electronic web-based record that can be shared with key healthcare professionals.

Efficacy of Bacillus thuringiensis Cry3Aa protoxin and protease inhibitors against coleopteran storage pests.

BACKGROUND: Environmental impacts and resistance to insecticides pose serious challenges to stored-product insect and other types of pest control. Insect-resistant transgenic grain is a potential alternative to fumigants, but candidate control proteins are needed, especially for coleopterans. Therefore, we evaluated the efficacy of a coleopteran-active toxin, Bacillus thuringiensis Cry3Aa, with or without protease inhibitors, in laboratory feeding assays against coleopteran storage pests. RESULTS: In a comparison of the toxicity of Cry3Aa protoxin towards three species of coleopteran storage pests, Tenebrio molitor L. was found to be most sensitive, Tribolium castaneum (Herbst.) was most refractory and Rhyzopertha dominica F. displayed an intermediate response. For R. dominica, Cry3Aa combined with 3500 mg potato carboxypeptidase inhibitor or 5000 mg aprotinin kg(-1) diet resulted in both delayed development and increased mortality. Potato carboxypeptidase inhibitor and bovine aprotinin reduced the LC(50) of Cry3Aa for R. dominica two- and threefold respectively. Cry3Aa treatment resulted in fewer progeny from R. dominica, and progeny was further reduced when the protoxin was combined with potato carboxypeptidase inhibitor. CONCLUSIONS: These data support the hypothesis that a combination of Cry3Aa protoxin and protease inhibitors, particularly a potato carboxypeptidase inhibitor, may have applications in control strategies for preventing damage to stored products and grains by coleopteran pests.

Changes in the V3 region of gp120 contribute to unusually broad coreceptor usage of an HIV-1 isolate from a CCR5 Delta32 heterozygote.

Heterozygosity for the CCR5 Delta32 allele is associated with delayed progression to AIDS in human immunodeficiency virus type 1 (HIV-1) infection. Here we describe an unusual HIV-1 isolate from the blood of an asymptomatic individual who was heterozygous for the CCR5 Delta32 allele and had reduced levels of CCR5 expression. The primary virus used CCR5, CXCR4, and an unusually broad range of alternative coreceptors to enter transfected cells. However, only CXCR4 and CCR5 were used to enter primary T cells and monocyte-derived macrophages, respectively. Full-length Env clones had an unusually long V1/V2 region and rare amino acid variants in the V3 and C4 regions. Mutagenesis studies and structural models suggested that Y308, D321, and to a lesser extent K442 and E444, contribute to the broad coreceptor usage of these Envs, whereas I317 is likely to be a compensatory change. Furthermore, database analysis suggests that covariation can occur at positions 308/317 and 308/321 in vivo. Y308 and D321 reduced dependence on the extracellular loop 2 (ECL2) region of CCR5, while these residues along with Y330, K442, and E444 enhanced dependence on the CCR5 N-terminus compared to clade B consensus residues at these positions. These results suggest that expanded coreceptor usage of HIV-1 can occur in some individuals without rapid progression to AIDS as a consequence of changes in the V3 region that reduce dependence on the ECL2 region of CCR5 by enhancing interactions with conserved structural elements in G-protein-coupled receptors.

Increased CCR5 affinity and reduced CCR5/CD4 dependence of a neurovirulent primary human immunodeficiency virus type 1 isolate.

Most human immunodeficiency virus type 1 (HIV-1) viruses in the brain use CCR5 as the principal coreceptor for entry into a cell. However, additional phenotypic characteristics are necessary for HIV-1 neurotropism. Furthermore, neurotropic strains are not necessarily neurovirulent. To better understand the determinants of HIV-1 neurovirulence, we isolated viruses from brain tissue samples from three AIDS patients with dementia and HIV-1 encephalitis and analyzed their ability to induce syncytia in monocyte-derived macrophages (MDM) and neuronal apoptosis in primary brain cultures. Two R5X4 viruses (MACS1-br and MACS1-spln) were highly fusogenic in MDM and induced neuronal apoptosis. The R5 viruses UK1-br and MACS2-br are both neurotropic. However, only UK1-br induced high levels of fusion in MDM and neuronal apoptosis. Full-length Env clones from UK1-br required lower CCR5 and CD4 levels than Env clones from MACS2-br to function efficiently in cell-to-cell fusion and single-round infection assays. UK1-br Envs also had a greater affinity for CCR5 than MACS2-br Envs in binding assays. Relatively high levels of UK1-br and MACS2-br Envs bound to CCR5 in the absence of soluble CD4. However, these Envs could not mediate CD4-independent infection, and MACS2-br Envs were unable to mediate fusion or infection in cells expressing low levels of CD4. The UK1-br virus was more resistant than MACS2-br to inhibition by the CCR5-targeted inhibitors TAK-779 and Sch-C. UK1-br was more sensitive than MACS2-br to neutralization by monoclonal antibodies (2F5 and immunoglobulin G1b12 [IgG1b12]) and CD4-IgG2. These results predict the presence of HIV-1 variants with increased CCR5 affinity and reduced dependence on CCR5 and CD4 in the brains of some AIDS patients with central nervous system disease and suggest that R5 variants with increased CCR5 affinity may represent a pathogenic viral phenotype contributing to the neurodegenerative manifestations of AIDS.

HIV-1 escape from a small molecule, CCR5-specific entry inhibitor does not involve CXCR4 use.

To study HIV-1 escape from a coreceptor antagonist, the R5 primary isolate CC1/85 was passaged in peripheral blood mononuclear cells with increasing concentrations of the CCR5-specific small molecule inhibitor, AD101. By 19 passages, an escape mutant emerged with a >20,000-fold resistance to AD101. This virus was cross-resistant to a related inhibitor, SCH-C, and partially resistant to RANTES but still sensitive to CCR5-specific mAbs. The resistant phenotype was stable; the mutant virus retained AD101 resistance during nine additional passages of culture in the absence of inhibitor. Replication of the escape mutant in peripheral blood mononuclear cells completely depended on CCR5 expression and did not occur in cells from CCR5-Delta32 homozygous individuals. The escape mutant was unable to use CXCR4 or any other tested coreceptor to enter transfected cells. Acquisition of CXCR4 use is not the dominant in vitro escape pathway for a small molecule CCR5 entry inhibitor. Instead, HIV-1 acquires the ability to use CCR5 despite the inhibitor, first by requiring lower levels of CCR5 for entry and then probably by using the drug-bound form of the receptor.