Automatic detection of COVID-19 from chest radiographs using deep learning.

INTRODUCTION: The breakdown of a deadly infectious disease caused by a newly discovered coronavirus (named SARS n-CoV2) back in December 2019 has shown no respite to slow or stop in general. This contagious disease has spread across different lengths and breadths of the globe, taking a death toll to nearly 700 k by the start of August 2020. The number is well expected to rise even more significantly. In the absence of a thoroughly tested and approved vaccine, the onus primarily lies on obliging to standard operating procedures and timely detection and isolation of the infected persons. The detection of SARS n-CoV2 has been one of the core concerns during the fight against this pandemic. To keep up with the scale of the outbreak, testing needs to be scaled at par with it. With the conventional PCR testing, most of the countries have struggled to minimize the gap between the scale of outbreak and scale of testing. METHOD: One way of expediting the scale of testing is to shift to a rigorous computational model driven by deep neural networks, as proposed here in this paper. The proposed model is a non-contact process of determining whether a subject is infected or not and is achieved by using chest radiographs; one of the most widely used imaging technique for clinical diagnosis due to fast imaging and low cost. The dataset used in this work contains 1428 chest radiographs with confirmed COVID-19 positive, common bacterial pneumonia, and healthy cases (no infection). We explored the pre-trained VGG-16 model for classification tasks in this. Transfer learning with fine-tuning was used in this study to train the network on relatively small chest radiographs effectively. RESULTS: Initial experiments showed that the model achieved promising results and can be significantly used to expedite COVID-19 detection. The experimentation showed an accuracy of 96% and 92.5% in two and three output class cases, respectively. CONCLUSION: We believe that this study could be used as an initial screening, which can help healthcare professionals to treat the COVID patients by timely detecting better and screening the presence of disease. IMPLICATION FOR PRACTICE: Its simplicity drives the proposed deep neural network model, the capability to work on small image dataset, the non-contact method with acceptable accuracy is a potential alternative for rapid COVID-19 testing that can be adapted by the medical fraternity considering the criticality of the time along with the magnitudes of the outbreak.

Therapeutically effective antibodies against amyloid-beta peptide target amyloid-beta residues 4-10 and inhibit cytotoxicity and fibrillogenesis.

Immunization of transgenic mouse models of Alzheimer disease using amyloid-beta peptide (Abeta) reduces both the Alzheimer disease-like neuropathology and the spatial memory impairments of these mice. However, a therapeutic trial of immunization with Abeta42 in humans was discontinued because a few patients developed significant meningo-encephalitic cellular inflammatory reactions. Here we show that beneficial effects in mice arise from antibodies selectively directed against residues 4-10 of Abeta42, and that these antibodies inhibit both Abeta fibrillogenesis and cytotoxicity without eliciting an inflammatory response. These findings provide the basis for improved immunization antigens as well as attempts to design small-molecule mimics as alternative therapies.

Object recognition memory and cholinergic parameters in mice expressing human presenilin 1 transgenes.

Most autosomal dominant forms of Alzheimer disease (AD) are related to missense mutations in the human presenilin (PS) 1 gene. Although the underlying mechanisms associated with pathophysiology of AD have yet to be clearly established, pathogenic mutations in the PS1 gene influence the processing of beta-amyloid precursor protein, leading to increased production and deposition of highly fibrillogenic amyloid beta(1-42) peptide in the brains of AD patients. As cognitive dysfunction in AD is associated with a dramatic loss of cholinergic innervation particularly in the hippocampus and neocortex, we investigated learning and cholinergic neurochemistry in transgenic mice expressing pathogenic mutant L286V or wild-type(wt) human PS1 transgenes. Relative to wt, the L286V PS1 transgenic mice exhibited reduced sensorimotor activity and marked deterioration of object memory between 3 and 5 h after the first encounter. Activity of the biosynthetic enzyme choline acetyltransferase was not altered in the hippocampus, frontoparietal cortex, or striatum of mutant transgenic mice relative to wt transgenic or littermate nontransgenic controls. No differences in the densities of M1/[3H]pirenzepine, M2/[3H]AF-DX 384, or alpha(7) nicotinic/125I-alpha-bungarotoxin receptor binding sites were evident in any brain regions among L286V PS1 transgenic, wt PS1 transgenic, and littermate nontransgenic controls. These results suggest that overexpression of a mutated PS1 gene induces a subtle alteration in object memory without affecting cholinergic neurochemistry.

Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695.

We have created early-onset transgenic (Tg) models by exploiting the synergistic effects of familial Alzheimer's disease mutations on amyloid beta-peptide (Abeta) biogenesis. TgCRND8 mice encode a double mutant form of amyloid precursor protein 695 (KM670/671NL+V717F) under the control of the PrP gene promoter. Thioflavine S-positive Abeta amyloid deposits are present at 3 months, with dense-cored plaques and neuritic pathology evident from 5 months of age. TgCRND8 mice exhibit 3,200-4,600 pmol of Abeta42 per g brain at age 6 months, with an excess of Abeta42 over Abeta40. High level production of the pathogenic Abeta42 form of Abeta peptide was associated with an early impairment in TgCRND8 mice in acquisition and learning reversal in the reference memory version of the Morris water maze, present by 3 months of age. Notably, learning impairment in young mice was offset by immunization against Abeta42 (Janus, C., Pearson, J., McLaurin, J., Mathews, P. M., Jiang, Y., Schmidt, S. D., Chishti, M. A., Horne, P., Heslin, D., French, J., Mount, H. T. J., Nixon, R. A., Mercken, M., Bergeron, C., Fraser, P. E., St. George-Hyslop, P., and Westaway, D. (2000) Nature 408, 979-982). Amyloid deposition in TgCRND8 mice was enhanced by the expression of presenilin 1 transgenes including familial Alzheimer's disease mutations; for mice also expressing a M146L+L286V presenilin 1 transgene, amyloid deposits were apparent by 1 month of age. The Tg mice described here suggest a potential to investigate aspects of Alzheimer's disease pathogenesis, prophylaxis, and therapy within short time frames.

New developments in animal models of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by deterioration in mental function leading to dementia, deposition of amyloid plaques and neurofibrillary tangles (NFTs), and neuronal loss. The major component of plaques is the amyloid-beta peptide (A beta), whereas NFTs are assemblies of hyperphosphorylated forms of the microtubule-associated protein tau. Electron microscopy of NFTs reveals structures known as paired helical filaments (PHFs). In familial AD (FAD), mutations in three distinct genes drive A beta synthesis by favoring endoproteolytic secretase cleavages that liberate A beta from the Alzheimer beta-amyloid precursor protein (APP). This suggests that excess A beta initiates a pathogenic cascade in humans that culminates in all the pathologic and cellular hallmarks of AD. Building upon the knowledge of FAD mutations, incremental technical advances have now allowed reproduceable creation of APP transgenic mice that exhibit AD-like amyloid pathology and A beta burdens. These transgenic mouse lines also exhibit deficits in spatial reference and working memory, with immunization against A beta abrogating both AD-associated phenotypes. Besides establishing a proof of principle for A beta-directed therapies, these findings suggest a potential to identify individual elements in the pathogenic pathway that lead to cognitive dysfunction. Furthermore, transgenic APP mice with potent amyloid deposition will likely form a beach-head to capture the final elements of AD neuropathology--cell loss and NFTs composed of PHFs--that are missing from current transgenic models.

Spatial learning in transgenic mice expressing human presenilin 1 (PS1) transgenes.

Dominant mutations in the Presenilin 1 gene are linked to an aggressive, early-onset form of familial Alzheimer's Disease (FAD). Spatial memory of transgenic (Tg) mice expressing either mutant (lines Tg(M146L)1, Tg(M146L)76, Tg(L286V)198) or wild type (line Tg(PS1wt)195) human PS1 transgenes was investigated in the Morris water maze (WM) test at 6 and 9 months of age. The results showed that the mutated Tg mice had increased swim speed when compared to non-Tg littermates or Tg PS1 wild type mice. The swim speed difference did not, however, significantly affect the spatial learning in the WM test and all groups showed comparable search paths during training and similar spatial bias during probe trials. When re-tested at 9 months, all mice showed significantly improved learning acquisition of spatial information. The lack of progressive spatial learning impairment in mice expressing the mutated human PS1 transgene in the WM does not preclude impairments in other cognitive tasks but suggests that full phenotypic expression of mutant PS1 alleles may require co-expression of human versions of other AD-associated genes.

Copper(II)-induced conformational changes and protease resistance in recombinant and cellular PrP. Effect of protein age and deamidation.

While PrP(C) rearranges in the area of codons 104-113 to form PrP(Sc) during prion infections, the events that initiate sporadic Creutzfeldt-Jakob disease are undefined. As Cu(II) is a putative ligand for PrP(C) and has been implicated in the pathogenesis of Creutzfeldt-Jakob disease and other neurodegenerative diseases, we investigated the structural effects of binding. Incubation of brain microsomes with Cu(II) generated approximately 30-kDa proteinase K-resistant PrP. Cu(II) had little effect on fresh recombinant PrP23-231, but aged protein characterized by conversion of Asn-107 to Asp decreased alpha-helical content by approximately 30%, increased beta-sheet content 100%, formed aggregates, and acquired proteinase K resistance in the presence of Cu(II). These transitions took place without need for acid pH, organic solvents, denaturants, or reducing agents. Since conversion of Asn to Asp proceeds by a spontaneous pathway involving deamidation, our data suggest that covalent variants of PrP(C) arising in this manner may, in concert with Cu(II), generate PrP(Sc)-like species capable of initiating sporadic prion disease.

A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease.

Much evidence indicates that abnormal processing and extracellular deposition of amyloid-beta peptide (A beta), a proteolytic derivative of the beta-amyloid precursor protein (betaAPP), is central to the pathogenesis of Alzheimer's disease (reviewed in ref. 1). In the PDAPP transgenic mouse model of Alzheimer's disease, immunization with A beta causes a marked reduction in burden of the brain amyloid. Evidence that A beta immunization also reduces cognitive dysfunction in murine models of Alzheimer's disease would support the hypothesis that abnormal A beta processing is essential to the pathogenesis of Alzheimer's disease, and would encourage the development of other strategies directed at the 'amyloid cascade'. Here we show that A beta immunization reduces both deposition of cerebral fibrillar A beta and cognitive dysfunction in the TgCRND8 murine model of Alzheimer's disease without, however, altering total levels of A beta in the brain. This implies that either a approximately 50% reduction in dense-cored A beta plaques is sufficient to affect cognition, or that vaccination may modulate the activity/abundance of a small subpopulation of especially toxic A beta species.

Ataxia in prion protein (PrP)-deficient mice is associated with upregulation of the novel PrP-like protein doppel.

The novel locus Prnd is 16 kb downstream of the mouse prion protein (PrP) gene Prnp and encodes a 179 residue PrP-like protein designated doppel (Dpl). Prnd generates major transcripts of 1.7 and 2.7 kb as well as some unusual chimeric transcripts generated by intergenic splicing with Prnp. Like PrP, Dpl mRNA is expressed during embryogenesis but, in contrast to PrP, it is expressed minimally in the CNS. Unexpectedly, Dpl is upregulated in the CNS of two PrP-deficient (Prnp(0/0)) lines of mice, both of which develop late-onset ataxia, suggesting that Dpl may provoke neurodegeneration. Dpl is the first PrP-like protein to be described in mammals, and since Dpl seems to cause neurodegeneration similar to PrP, the linked expression of the Prnp and Prnd genes may play a previously unrecognized role in the pathogenesis of prion diseases or other illnesses.

Syrian hamster prion protein (PrP(C)) is expressed in photoreceptor cells of the adult retina.

PrP(C), the cellular isoform of the prion protein (PrP) serves as a precursor to abnormal PrP isoforms which accumulate in diseases such as scrapie in sheep, and Creutzfeldt-Jakob disease in humans. Since prions can replicate in photoreceptors we surmised that PrP(C) must be expressed in these cells. Accordingly, monoclonal antisera directed against two epitopes of hamster PrP(C) produced retinal immunostaining in hamsters, and in mice bearing a hamster PrP transgene. Immunostaining was most prominent in the inner and outer segments of rod photoreceptors, coinciding with the earliest site of pathologic changes in scrapie-infected hamsters. These data define PrP(C) expression in an experimentally-accessible population of neurons and suggest that the retina may comprise a useful system for studying the biology of wild-type and mutant prion proteins.

Aroclors 1254 and 1260 reduce dopamine concentrations in rat striatal slices.

Striatal slices from adult male Wistar-derived rats were exposed to a 1:1 mixture of Aroclor 1254:1260 at concentrations in media of 10, 20, 40, 60 or 100 ppm for 6 hr. Following exposure, slices and media were analyzed by high-performance liquid chromatography for dopamine (DA) and its metabolites. PCBs caused a significant dose-dependent decrease in slice DA content at concentrations greater than 20 ppm. Media concentrations of DA and its metabolites were significantly increased by PCB exposure greater than 60 ppm, indicating that, in addition to their suggested role in inhibiting DA synthesis, PCBs may interfere with either vesicular storage or release of DA. These data suggest that in addition to the recognized action of PCBs in inhibiting tyrosine hydroxylase, PCBs may also interfere with the vesicular monoamine transporter, and thereby suggest an additional mechanism by which DA concentrations and metabolism may be altered by PCB exposure.

Pathomorphological studies in European bison (Bison bonasus Linnaeus, 1758) with seropositive reaction to Coxiella burnetii.

Comprehensive serological and histopathological examinations of 47 free living European bison (Bison bonasus Linnaeus, 1758) were performed. Of these animals, 36 were serologically positive due to Coxiella burnetii, which confirmed the presence of Q fever epizootic foci in this population of wild animals in Poland. The presence of multiple foci of mononuclear cells typical for Q fever was a consistent finding in all tissues of the majority of C. burnetii seropositive animals under study. Pathomorphological changes observed in myocardium as the focal coagulation necrosis, and in kidneys, resembled the glomerular lesion observed in humans with Q fever, as well as in the experimental Q-fever infections in laboratory animals. These changes were absent in bison showing a C. burnetii seronegative reaction.

Sero-diagnosis for viral hepatitis in 93 patients admitted with acute hepatitis in three different teaching hospitals in Lahore.

Serodiagnosis was done in 93 patients admitted with acute viral hepatitis (AVH) to three teaching hospitals in Lahore. Five (5.4%) had hepatitis A, 39 (41.9%) hepatitis B (2 of these were anti delta positive) [see erratum notice], 44 (47.3%) probable hepatitis E and 3(3.2%) had HAV/HBV co-infection. Antibody to hepatitis C (anti HCV) was detected in 6 patients (6.4%); 2 with HBV and 4 with probable HEV infection. Excluding 39 patients with hepatitis B and 3 with HBV as part of co-infection, there was evidence of previous HBV infection in 39 out of the remaining 51 patients. In the subset of 6 children, 3 had hepatitis A and 3 hepatitis E. Of these, 5 had evidence of previous exposure to HBV and one was also positive for anti HCV. Our results are suggestive of a strong background of HBV infection raising concern about its chronic sequelae in the community.

Hepatic and renal ultrastructural changes in cockerels exposed to cadmium chloride and subsequent interaction with organophosphate insecticide.

Ultrastructural alterations of the liver and kidneys of cockerels exposed to 100 ppm of cadmium chloride (CdCl2) and subsequent interaction with an organophosphorus compound (methylobromofenvinphos) were studied. Four groups, each consisting of 25 birds, included 100 ppm of CdCl2 in drinking water for 4 weeks (Group A), 100 ppm of CdCl2 for 4 weeks followed by a single dose of 240 mg/kg of methylobromofenvinphos (IPO 63 compound) (Group B), single dose of 240 mg/kg of IPO 63 compound (Group C), and untreated control (Group D). Three birds from each group were sacrificed 24 hr post treatment with IPO 63 compound and tissue pieces were collected for electron microscopic study. Ultrastructural changes in hepatocytes included swollen mitochondria with cavitation, dilated rough endoplasmic reticulum, numerous lysosomal bodies, myelin figures, depletion of glycogen granules, and numerous vacuoles containing degenerated membranes in birds that interacted with CdCl2. In a few cells the nuclei were markedly damaged with dilation of envelope. Renal corpuscles of CdCl2 showed irregular foot processes and thickening of the glomerular basement membrane. The proximal tubular cells of CdCl2 birds showed marked ultrastructural alterations, including numerous lysosomal bodies, few fat droplets, membrane bound vacuoles studded with polyribosomes, swollen mitochondria with fragmented cristae surrounded by rough endoplasmic reticulum, vacuoles containing myelin figures, and damaged nuclei with dilated envelope. Minor ultrastructural alterations were observed in the liver and kidneys of birds treated with cadmium alone and of those treated only with IPO 63 compound. These observations suggest that treatment with CdCl2 and then subsequent interaction with IPO 63 compound causes hepatic and renal damage that appears to be additive.

Ultrastructural alterations produced in cockerels after mercuric chloride toxicity and subsequent interaction with an organophosphate insecticide.

Ultrastructural changes of liver and kidneys of cockerels exposed to mercuric chloride and subsequent interaction with methylobromofenvinphos (IPO 63 compound) were studied. Group A birds were treated for 4 weeks with 300 ppm mercuric chloride in drinking water; Group B birds were treated for 4 weeks with mercuric chloride followed by single oral dose of 240 mg/kg of IPO 63; Group C 240 mg/kg IPO 63 only; and Group D, unexposed controls. Hepatocytes of mercury-IPO 63 interaction group B showed large lysosomes containing myelin bodies, swollen mitochondria with cristeolysis, dilated endoplasmic reticulum and numerous vacuoles containing granular material. Mercury-intoxicated birds showed similar but less severe changes, whereas IPO 63-treated birds showed accumulation of glycogen granules, fat droplets, and few lysosomal bodies as well as other changes. Renal corpuscles of kidney from mercury-IPO 63 interaction birds revealed minor ultrastructural changes as vacuolation, swollen mitochondria of podocytes and slight thickening of the glomerular basement membrane. Proximal tubular cells showed extreme damage such as, microvillar loss, dilation of endoplasmic reticulum, accumulation of lysosomal bodies, glycogen granules, myelin figures, swollen mitochondria with granular material, numerous vacuoles containing degenerated membranous organelles and distorted, pyknotic nucleus with marked dilation of nuclear membrane. Mercury intoxicated birds showed similar but less pronounced changes in tubules. These observations suggest that the effect of mercuric chloride toxicity and then interaction with an organophosphorus insecticide causes extreme damage to hepatic and renal cells that appears to be additive.