Machine learning methods offer great promise for fast and accurate detection and prognostication of coronavirus disease 2019 (COVID-19) from standard-of-care chest radiographs (CXR) and chest computed tomography (CT) images. Many articles have been published in 2020 describing new machine learning-based models for both of these tasks, but it is unclear which are of potential clinical utility. In this systematic review, we consider all published papers and preprints, for the period from 1 January 2020 to 3 October 2020, which describe new machine learning models for the diagnosis or prognosis of COVID-19 from CXR or CT images. All manuscripts uploaded to bioRxiv, medRxiv and arXiv along with all entries in EMBASE and MEDLINE in this timeframe are considered. Our search identified 2,212 studies, of which 415 were included after initial screening and, after quality screening, 62 studies were included in this systematic review. Our review finds that none of the models identified are of potential clinical use due to methodological flaws and/or underlying biases. This is a major weakness, given the urgency with which validated COVID-19 models are needed. To address this, we give many recommendations which, if followed, will solve these issues and lead to higher-quality model development and well-documented manuscripts.

The molecular weight cutoff for glomerular filtration is thought to be 30-50 kDa. Here we report rapid and efficient filtration of molecules 10-20 times that mass and a model for the mechanism of this filtration. We conducted multimodal imaging studies in mice to investigate renal clearance of a single-walled carbon nanotube (SWCNT) construct covalently appended with ligands allowing simultaneous dynamic positron emission tomography, near-infrared fluorescence imaging, and microscopy. These SWCNTs have a length distribution ranging from 100 to 500 nm. The average length was determined to be 200-300 nm, which would yield a functionalized construct with a molecular weight of ∼350-500 kDa. The construct was rapidly (t 1/2 ∼ 6 min) renally cleared intact by glomerular filtration, with partial tubular reabsorption and transient translocation into the proximal tubular cell nuclei. Directional absorption was confirmed in vitro using polarized renal cells. Active secretion via transporters was not involved. Mathematical modeling of the rotational diffusivity showed the tendency of flow to orient SWCNTs of this size to allow clearance via the glomerular pores. Surprisingly, these results raise questions about the rules for renal filtration, given that these large molecules (with aspect ratios ranging from 100:1 to 500:1) were cleared similarly to small molecules. SWCNTs and other novel nanomaterials are being actively investigated for potential biomedical applications, and these observations-that high aspect ratio as well as large molecular size have an impact on glomerular filtration-will allow the design of novel nanoscalebased therapeutics with unusual pharmacologic characteristics.multimodal imaging | nanotechnology | renal C arbon nanotubes (CNTs) have interesting properties and have been proposed as novel components of drugs and devices in pharmaceutical and biomedical applications (1). CNTs have unique intrinsic physical, chemical, electronic, thermal, and optical properties and can be chemically modified (with, e.g., targeting ligands, magnetic, radioactive, fluorescent, and chemotherapeutic moieties) to exhibit additional extrinsic properties (2-4). Pharmacokinetic (PK) studies of covalently functionalized single-wall CNTs (SWCNTs) (5-9) and multiwall (MWCNTs) (10-12) have reported a short blood compartment half-life (1-3 h) and limited tissue (kidneys, liver, and spleen) accumulation and renal excretion. Clearance via renal mechanisms is significant (13), because it provides the opportunity for the host to eliminate SWCNTs, allowing potential therapeutic and diagnostic applications in vivo. The elimination of noncovalently modified SWCNTs has been reported to favor the hepatobiliary route, with evidence of a minor role for the renal route (14).Renal clearance of solutes occurs through a combination of glomerular filtration, active tubular secretion, and passive tubular reabsorption (15). In previous work, we reported radioactivity in the renal cortex and in the urine within 1 h of administration of radiolabeled...

The development of novel multimodality imaging agents and techniques represents the current frontier of research in the field of medical imaging science. However, the combination of nuclear tomography with optical techniques has yet to be established. Here, we report the use of the inherent optical emissions from the decay of radiopharmaceuticals for Cerenkov luminescence imaging (CLI) of tumors in vivo and correlate the results with those obtained from concordant immuno-PET studies. Methods: In vitro phantom studies were used to validate the visible light emission observed from a range of radionuclides including the positron emitters 18 F, 64 Cu, 89 Zr, and 124 I; b-emitter 131 I; and a-particle emitter 225 Ac for potential use in CLI. The novel radiolabeled monoclonal antibody 89 Zr-desferrioxamine B [DFO]-J591 for immuno-PET of prostate-specific membrane antigen (PSMA) expression was used to coregister and correlate the CLI signal observed with the immuno-PET images and biodistribution studies. Results: Phantom studies confirmed that Cerenkov radiation can be observed from a range of positron-, b-, and a-emitting radionuclides using standard optical imaging devices. The change in light emission intensity versus time was concordant with radionuclide decay and was also found to correlate linearly with both the activity concentration and the measured PET signal (percentage injected dose per gram). In vivo studies conducted in male severe combined immune deficient mice bearing PSMA-positive, subcutaneous LNCaP tumors demonstrated that tumor-specific uptake of 89 Zr-DFO-J591 could be visualized by both immuno-PET and CLI. Optical and immuno-PET signal intensities were found to increase over time from 24 to 96 h, and biodistribution studies were found to correlate well with both imaging modalities. Conclusion: These studies represent the first, to our knowledge, quantitative assessment of CLI for measuring radiotracer uptake in vivo. Many radionuclides common to both nuclear tomographic imaging and radiotherapy have the potential to be used in CLI. The value of CLI lies in its ability to image radionuclides that do not emit either positrons or g-rays and are, thus, unsuitable for use with current nuclear imaging modalities. Optical imaging of Cerenkov radiation emission shows excellent promise as a potential new imaging modality for the rapid, high-throughput screening of radiopharmaceuticals. In the field of medical imaging science, the concept of multimodality is providing the driving force for the development of the next generation of imaging techniques. The latest hybrid systems such as PET/CT and PET/MRI are transforming the clinical management of cancer patients by consolidating the noninvasive localization and temporal quantification of changes in tissue function and physiology available from PET, with the high-resolution anatomic maps provided by CT or MRI (1,2).In contrast to the immediate clinical impact of nuclear tomographic imaging, optical methods such fluorescencemediated tomography and bioluminescen...

Long-term survival still eludes most patients with leukemia and non-Hodgkin’s lymphoma. No approved therapies target the hallmark of the B cell, its mIgM, also known as the B-cell receptor (BCR). Aptamers are small oligonucleotides that can specifically bind to a wide range of target molecules and offer some advantages over antibodies as therapeutic agents. Here, we report the rational engineering of aptamer TD05 into multimeric forms reactive with the BCR that may be useful in biomedical applications. Systematic truncation of TD05 coupled with modification with locked nucleic acids (LNA) increased conformational stability and nuclease resistance. Trimeric and tetrameric versions with optimized polyethyleneglycol (PEG) linker lengths exhibited high avidity at physiological temperatures both in vitro and in vivo. Competition and protease studies showed that the multimeric, optimized aptamer bound to membrane-associated human mIgM, but not with soluble IgM in plasma, allowing the possibility of targeting leukemias and lymphomas in vivo. The B-cell specificity of the multivalent aptamer was confirmed on lymphoma cell lines and fresh clinical leukemia samples. The chemically engineered aptamers, with significantly improved kinetic and biochemical features, unique specificity and desirable pharmacological properties, may be useful in biomedical applications.

BackgroundReceptor activator of NFkB (RANK), its ligand (RANKL) and the decoy receptor of RANKL (osteoprotegerin, OPG) play a pivotal role in bone remodeling by regulating osteoclasts formation and activity. RANKL stimulates migration of RANK-expressing tumor cells in vitro, conversely inhibited by OPG.Materials and MethodsWe examined mRNA expression levels of RANKL/RANK/OPG in a publicly available microarray dataset of 295 primary breast cancer patients. We next analyzed RANK expression by immunohistochemistry in an independent series of 93 primary breast cancer specimens and investigated a possible association with clinicopathological parameters, bone recurrence and survival.ResultsMicroarray analysis showed that lower RANK and high OPG mRNA levels correlate with longer overall survival (P = 0.0078 and 0.0335, respectively) and disease-free survival (P = 0.059 and 0.0402, respectively). Immunohistochemical analysis of RANK showed a positive correlation with the development of bone metastases (P = 0.023) and a shorter skeletal disease-free survival (SDFS, P = 0.037). Specifically, univariate analysis of survival showed that “RANK-negative” and “RANK-positive” patients had a SDFS of 105.7 months (95% CI: 73.9–124.4) and 58.9 months (95% CI: 34.7–68.5), respectively. RANK protein expression was also associated with accelerated bone metastasis formation in a multivariate analysis (P = 0.029).ConclusionsThis is the first demonstration of the role of RANK expression in primary tumors as a predictive marker of bone metastasis occurrence and SDFS in a large population of breast cancer patients.

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BackgroundAssessment of tumor size changes is crucial in clinical trials and patient care. We compared imatinib-induced volume changes of liver metastases (LM) from gastro-intestinal stromal tumors (GIST) to RECIST and Choi criteria and their association with overall survival (OS).MethodsLM from 84 GIST patients (training and validation set) were evaluated using manual and semi-automated Computed Tomography measurements at baseline, after 3, 6 and 12 months of imatinib. The ability of uni-dimensional (1D) and three-dimensional (3D) measurements to detect size changes (increase/decrease) ≥20% was evaluated. Volumetric response cut-offs were derived from minimally relevant changes (+20/−30%) by RECIST, considering lesions as spherical or ellipsoidal.Results3D measurements detected size changes ≥20% more frequently than 1D at every time-point (P≤0.008). 3D and Choi criteria registered more responses than RECIST at 3 and 6 months for 3D-spheres (P≤0.03) and at all time-points for 3D-ellipsoids and Choi criteria (P<0.001). Progressive disease by 3D criteria seems to better correlate to OS at late time-points than other criteria.ConclusionVolume criteria (especially ellipsoids) classify a higher number of patients as imatinib-responders than RECIST. Volume discriminates size changes better than diameter in GIST and constitutes a feasible and robust method to evaluate response and predict patient benefit.

Single-wall carbon nanotubes present unique opportunities for drug delivery, but have not advanced into the clinic. Differential nanotube accretion and clearance from critical organs have been observed, but the mechanism not fully elucidated. The liver has a complex cellular composition that regulates a range of metabolic functions and coincidently accumulates most particulate drugs. Here we provide the unexpected details of hepatic processing of covalently functionalized nanotubes including receptor-mediated endocytosis, cellular trafficking and biliary elimination. Ammonium-functionalized fibrillar nanocarbon is found to preferentially localize in the fenestrated sinusoidal endothelium of the liver but not resident macrophages. Stabilin receptors mediate the endocytic clearance of nanotubes. Biocompatibility is evidenced by the absence of cell death and no immune cell infiltration. Towards clinical application of this platform, nanotubes were evaluated for the first time in non-human primates. The pharmacologic profile in cynomolgus monkeys is equivalent to what was reported in mice and suggests that nanotubes should behave similarly in humans.